Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2012 Mar 23.
Published in final edited form as: Curr Drug Targets. 2010 Nov;11(11):1405–1412. doi: 10.2174/1389450111009011405

Potential Targets for Intervention in Radiation-Induced Heart Disease

M Boerma 1,*, M Hauer-Jensen 1
PMCID: PMC3311026  NIHMSID: NIHMS363328  PMID: 20583977

Abstract

Radiotherapy of thoracic and chest wall tumors, if all or part of the heart was included in the radiation field, can lead to radiation-induced heart disease (RIHD), a late and potentially severe side effect. RIHD presents clinically several years after irradiation and manifestations include accelerated atherosclerosis, pericardial and myocardial fibrosis, conduction abnormalities, and injury to cardiac valves. The pathogenesis of RIHD is largely unknown, and a treatment is not available. Hence, ongoing pre-clinical studies aim to elucidate molecular and cellular mechanisms of RIHD. Here, an overview of recent pre-clinical studies is given, and based on the results of these studies, potential targets for intervention in RIHD are discussed.

Keywords: Radiation, heart, animal models, transforming growth factor-beta, renin-angiotensin system, mast cells, endothelin system, sensory nerves

INTRODUCTION

There currently are millions of cancer survivors worldwide. In the Western world, about 40% of cancer survivors are at least 10 years past their cancer diagnosis. The number of long-term cancer survivors continues to grow worldwide with ongoing improvements in cancer therapy [1, 2]. Late side effects of cancer therapy, including secondary cancers and non-tumor tissue injury from radiation- and chemo-therapy, are a significant clinical problem among long-term cancer survivors. One of these late side effects of therapy, radiation-induced heart disease (RIHD) may occur after radiotherapy of thoracic and chest wall tumors whenever all or part of the heart was situated in the radiation field. The pathogenesis of RIHD is largely unknown, and a treatment is not available. Hence, ongoing pre-clinical studies aim to elucidate molecular and cellular mechanisms of RIHD and thereby identify potential targets for intervention. This review describes recent advances in the field of experimental RIHD.

CLINICAL SIGNIFICANCE OF RADIATION-INDUCED HEART DISEASE

RIHD is a late, relatively common and potentially severe side effect of radiotherapy of thoracic and chest wall tumors whenever all or part of the heart was included in the radiation field. RIHD presents clinically several years after irradiation and manifestations include accelerated atherosclerosis, pericardial and myocardial fibrosis, conduction abnormalities, and injury to cardiac valves [3, 4]. The disease is progressive and its incidence and severity increase with several factors, such as a higher radiation dose volume, younger age at the time of radiotherapy, a greater time elapsed since treatment, concomitant use of certain chemotherapeutic agents such as anthracyclines, obesity, and hypertension.

Many studies illustrate the clinical significance of RIHD, as reviewed by others [3, 5, 6]. In short, among patients treated with thoracic radiotherapy in the ’70s and ’80s a more than twofold increase in cardiovascular mortality is reported, both when compared with patients who did not receive radiotherapy and when compared with the general population [7, 8]. Although radiotherapy reduced the risk of recurrent cancer among breast cancer patients treated in this era, this benefit was offset by an increase in cardiac mortality [9–11]. Among breast cancer patients treated in the ’80s and ’90s a significant increase in the incidence of heart disease is found in left-sided breast cancer patients versus patients treated for right-sided breast cancer, indicating a significant adverse effect of radiation on the heart [12, 13].

Radiotherapy planning has improved over time, leading to reduced cardiac dose exposures during the last decades. However, recent studies indicate that problems persist; for instance, patients with Hodgkin’s Disease, lung cancer, esophageal and proximal gastric cancer may still receive a high dose of radiation to a small part of the heart or a lower dose of radiation to the whole heart [14–20]. In addition, adjuvant tangential radiotherapy, the common treatment of breast cancer in most parts of the world and in the recent past also in the western world, is known to expose small parts of the heart to doses >20 Gy in about 50% of left-sided breast cancer patients [21]. Although long-term effects of recent radiotherapy techniques cannot yet be determined [22], a high incidence of treatment-induced left ventricular perfusion defects is found in the first months to years after tangential radiotherapy for breast cancer [6, 23–25], indicating that the heart continues to be an organ at risk in certain groups of long-term cancer survivors. Moreover, although there is increasing use of concomitant therapies, the extent to which these therapies enhance the effects of radiation on normal tissues is not yet known.

Although RIHD is widely acknowledged as an impedement to quality of life for certain long-term cancer survivors, the pathogenesis of RIHD is largely unknown, and treatment is not yet available. As a means to identify potential targets for intervention strategies, several ongoing pre-clinical studies seek to unravel the molecular and cellular mechanisms of RIHD.

Pre-Clinical Models of Radiation-Induced Heart Disease

Studies on molecular and cellular mechanisms of RIHD in pre-clinical animal models are ongoing [26–31]. While transgenic mouse models are being used to study radiation-accelerated atherosclerosis [32, 33], rodents are usually not atherosclerosis-prone. Hence, few studies have used rat models to investigate radiation-induced coronary artery disease [34, 35]. The rat model of local heart irradiation, on the other hand, has been used successfully in pre-clinical studies of radiation-induced cardiomyopathy [36–39]. Localized heart irradiation in rats, both with a single dose and with a fractionated irradiation protocol, leads to reduced ventricular ejection fraction and restrictive diastolic filling as measured in vivo [40] and reduced cardiac output and increased diastolic stiffness when measured ex vivo [40–42]. Histopathological changes including myocardial degeneration (myocardial necrosis, accompanied by inflammation) and fibrosis. Radiation fibrosis and restrictive diastolic filling are commonly described in humans, although mainly after exposures with relatively high doses of radiation [4, 43–46]. The incidence of these alterations after lower dose exposures is not yet known. Data on dose-response relationships of RIHD in animal models are reviewed elsewhere [31, 47].

New technological advances have brought more detailed and minimally invasive methods to study cardiovascular changes in small laboratory animals. Techniques such as high-resolution ultrasound, magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT) are currently in use to assess cardiac structural and functional changes after exposure to radiation in small animals and will undoubtedly contribute to the progress made in the field of experimental RIHD in the coming years.

Below we outline the results obtained from pre-clinical studies designed to uncover mechanisms of RIHD. Studies have addressed the roles of endothelial injury, transforming growth factor-beta (TGF-β), the renin-angiotensin system (RAS), mast cells, the cardiac sensory nervous system, and endothelin-1 (ET-1) in experimental RIHD.

POTENTIAL MECHANISMS OF RIHD: REVIEW OF PRE-CLINICAL STUDIES

Endothelial Injury

Endothelial dysfunction has been shown to play an important role in the pathogenesis of normal tissue radiation injury, as reviewed elsewhere [48, 49]. Endothelial dysfunction is associated with a loss of thromboresistance and increased expression of chemokines and adhesion molecules and may lead to a pro-fibrotic and pro-inflammatory environment, all likely contributors to manifestations of radiation injury. Several studies suggest that endothelial dysfunction is occurring in RIHD, as experimental RIHD is associated with histopathological signs of microvascular injury and reduced myocardial capillary density [50], focal loss of endothelial alkaline phosphatase [27, 51], and increased expression and deposition of von Willebrand factor [52]. A recent study suggests that altered lipid profiles or other circulating factors may affect radiation-induced changes in the myocardial microvasculature [53]. Hence, although not yet tested in experimental models, pharmacological modifiers of endothelial function, such as statins and certain beta-blockers that are of benefit in many cardiovascular disease states may potentially reduce manifestations of RIHD.

TRANSFORMING GROWTH FACTOR-BETA

TGF-β is a pluripotent growth factor that controls many functions including cell proliferation and differentiation in many cell types. TGF-β plays an important role in cardiac hypertrophy and fibrosis [54, 55] and is considered a central growth player in radiation-induced normal tissue fibrosis [56–58] and radiation-induced vascular injury [59, 60]. Previous studies showed upregulation of TGF-β, both at the mRNA and the protein level, after local heart irradiation in the rat [61–63].

A TGF-β–inducing compound was used to investigate the role of TGF-β in RIHD in the rat. Radiation induced a significant increase in collagen deposition, which was more severe after TGF-β induction (unpublished data). To further analyze the role of TGF-β in RIHD, studies involving TGF-β signaling inhibition are being undertaken.

THE RENIN-ANGIOTENSIN SYSTEM

The RAS is a major regulatory system of cardiovascular and renal functions, regulating blood volume and vascular resistance. In addition to the first discovered circulatory RAS, recent evidence has shown that local tissue RAS plays a significant role in tissue homeostasis and the response to injury [64]. Angiotensin II (Ang II) is a small peptide formed in the RAS after the initial conversion of angiotensinogen to angiotensin I (Ang I) by the enzyme renin. The role of Ang II in cardiac pathophysiology is well known, having been the subject of numerous reviews [65–67]. Ang II can be generated from Ang I by several proteases, of which angiotensin converting enzyme (ACE) and mast cell chymase are the main converters [68]. Mast cell chymase seems of particular importance in the local extravascular generation of Ang II [69]. Interestingly, the local cardiac RAS interacts with many other systems in the heart, including the cardiac nervous systems and the endothelin system, and locally generated Ang II appears to contribute to cardiac hypertrophy and fibrosis [70, 71].

The role of RAS in radiation injury in organs other than the heart has been studied extensively and reviewed elsewhere [72, 73]. ACE inhibitors and antagonists of angiotensin type 1 receptors reduce experimental radiation injury in organs such as kidney, lung and brain [74–76]. Studies are emerging that show an upregulation of mediators of the cardiac RAS after local heart irradiation in animal models [77]. However, although the ACE inhibitor captopril reduced radiation injury in kidney, lung, and skin of rats [76, 78, 79], captopril did not prevent cardiac function loss in a rat model of RIHD [80]. Captopril, on the other hand, did reduce myocardial fibrosis and prevented left ventricular capillary density loss after local heart irradiation. However, these effects were suggested to be caused by properties of captopril other than ACE inhibition [80]. The role of RAS in cardiac radiation injury and the potential intervention in RIHD by pharmacological modification of RAS or by Ang II receptor inhibitors need further investigation.

MAST CELLS

As reviewed in detail elsewhere, mast cells are cells that derive from hematopoietic progenitor cells that release a wide range of cellular mediators, both via a mechanism that involves mast cell degranulation and via a constitutive pathway that does not involve degranulation [81]. Mast cells are resident to the heart and several lines of evidence support a role for mast cells in cardiac remodeling. For instance, mast cell hyperplasia is a common feature in human conditions associated with coronary atherosclerosis and myocardial fibrosis [82, 83] and in many animal models of heart disease [84], including RIHD [80, 85]. Increased mast cell numbers coincide with myocardial radiation injury, suggesting that mast cells may be involved in the development of RIHD.

Mast cell-deficient animal models have provided extensive insight into the role of mast cells in biological responses in vivo [86, 87]. Both mast cell development and maturation depend on the c-kit receptor, the protein-tyrosine kinase receptor that is specific for stem cell factor. Hence, several mast cell-deficient models are based on a mutation in the c-kit receptor or the stem cell factor gene [88–90]. Our laboratories have made use of the mast cell-deficient Ws/Ws rat model. Ws/Ws animals originate from a rat of the brown-Norway (BN)/fMai strain with a spontaneous 12-base deletion in the white spotting (Ws) gene locus encoding for the c-kit receptor [91]. As a result of their homozygous c-kit mutation, Ws/Ws rats lack functional mast cells, as well as melanocytes and interstitial cells of Cajal in the intestine, while their wildtype (+/+) litter mates show no abnormalities for these cell types [92]. Because the 12-base c-kit deletion is highly localized, Ws/Ws rats do not suffer from anemia and hematopoietic abnormalities characteristic of some of the mast cell-deficient mouse models [93, 94].

Ws/Ws rats and their +/+ litter mates were used to examine the role of cardiac mast cells in RIHD. Although the absence of mast cells diminished radiation-induced myocardial inflammation and degeneration, adverse changes in in vivo cardiac dimensions, myocardial fibrosis and ex vivo measures of myocardial stiffness were exacerbated at 6 months in the absence of mast cells [42]. These studies suggest that mast cells, in contrast to what had been the prevailing assumption, play a predominantly protective role in RIHD. Several studies have obtained similar results in other cardiac disease models [95, 96].

Mast cells interact with many cellular systems in the heart through their plethora of cellular mediators. Together with a reduction in radiation-induced cardiac function loss, mast cells were shown to be involved in cardiac radiation-induced upregulation of ET-1 and the sensory neuropeptide calcitonin gene related peptide (CGRP) [97], suggesting that mast cells may mediate their protective effects via interacttion with the endothelin system and/or the sensory nervous system.

CARDIAC SENSORY NERVOUS SYSTEM

Neuroimmune interactions are now widely accepted as important modulators of tissue homeostasis and injury. Mast cells are one of the main cell types involved in these neuroimmune interactions [98]. Mast cells are found in close proximity to nerve terminals or axons in many organs, including the heart [99, 100]. Moreover, mast cells may interact with neurons via specific adhesion molecules [101]. Interactions between mast cells and nerves on the molecular level have been extensively described and reviewed elsewhere [98, 102].

The interactions between mast cells and the cardiac nervous system are two-directional. While cardiac nerves influence mast cell function, mast cells in turn may affect nerve function. Mast cells express α- and β-adrenergic receptors [103, 104]. In normal rat myocardium, β-blockade is associated with increased mast cell degranulation and decreased collagen deposition [105]. In addition, sensory neuropeptides such as CGRP, substance P, and neuropeptide Y are able to induce mast cell degranulation [106–111], or enhance mast cell degranulation as induced by a second stimulus [112, 113]. Other neuropeptides, including somatostatin and vasoactive intestinal peptide, have been shown to inhibit mast cell degranulation [114, 115].

While cardiac nerves affect mast cell function, as described above, influence also occurs in the other direction. For example, mast cells produce nerve growth factor [116], an important factor in survival, growth, and differentiation of sensory and sympathetic neurons [117, 118]. Mast cell-derived proteases affect neuronal function via activation of proteinase-activated receptor-2 on the surface of neurons [119, 120]. Mast cell mediators, such as histamine and serotonin, influence the release of acetylcholine and norepinephrine from the autonomic nerve system [121], while mast cell enzymes can cleave certain sensory neuropeptides [122–124].

Albeit not intuitive, increasing evidence supports an important role for the sensory nervous system in the regulation of cardiac function. Cardiac sensory nerves act as detectors of myocardial ischemia and changes in potassium levels and pH. Hence, cardiac sensory denervation in diabetes mellitus patients contributes to silent myocardial ischemia [125, 126]. Cardiac sensory nerves play an additional protective role in the heart via the release of both nitric oxide and neuropeptides such as CGRP [127, 128]. CGRP is a potent vasodilator, but also has beneficial effects in the heart by local downregulation of tumor necrosis factor-alpha (TNF-α) and upregulation of insulin-like growth factor-1 (IGF-1) [129, 130]. Hence, CGRP plays a protective role in myocardial injury such as from ischemia-reperfusion and doxorubicin [131, 132]. Interestingly, both downregulation of TNF-α and upregulation of IGF-1 have also been shown to be protective in normal tissue radiation injury in organs other than the heart [133, 134].

The roles of the two sensory neuropeptides CGRP and substance P have been studied extensively in a rat model of radiation enteropathy [135]. Small intestine mRNA levels of both neuropeptides were upregulated after local irradiation. Administration of CGRP ameliorated radiation-induced intestine injury in rats, while a CGRP antagonist exacerbated injury, suggesting that CGRP played a protective role. Opposing results were obtained from the administration of substance P and a substance P receptor antagonist, suggesting that substance P played an aggravating role in intestinal radiation injury [135]. Considering the mast cell involvement in radiation-induced upregulation of CGRP in experimental RIHD and the known protective roles of CGRP in experimental radiation enteropathy and in myocardial injury from other causes, the role of this neuropeptide in RIHD deserves further investigation.

ENDOTHELIN SYSTEM

ET-1 is a 21-amino acid peptide that was first discovered as a potent vasoconstrictor but also has pro-inflammatory and pro-fibrotic properties [136, 137]. ET-1 is generated from its precursor, big endothelin, by several endothelin-converting enzymes and by mast cell-derived proteases [138]. ET-1 exerts its effects via two receptors, ETA and ETB, which are expressed by a wide variety of cell types in the heart [137, 139]. The role of ET-1 in cardiovascular pathology has been studied extensively [140, 141]. Short-term up-regulation of ET-1 and its receptors may serve as a mechanism to maintain cardiac function in certain cardiovascular diseases [142, 143]. Long-term up-regulation of the endothelin system, on the other hand, may have detrimental effects due to the vasopressor, pro-hypertrophic, and profibrotic properties of ET-1 [139, 144].

In vivo and in vitro evidence has demonstrated interacttions between mast cells and the endothelin system; however, the relationship between mast cells and the endothelin system is complex. Mast cells have been shown to both produce and degrade ET-1 [145–147]. The mast cell protease responsible for cleaving ET-1 and thereby protecting against ET-1 toxicity [40] may be carboxypeptidase A [148]. In addition, mast cells express ETA, which upon activation by ET-1 induces mast cell degranulation [149]. Mast cells contain proteases that can activate matrix metalloproteinase (MMP) [150, 151]. In the rat heart, ET-1 increases MMP activity by inducing cardiac mast cell degranulation [152].

In a rat model of chronic volume overload induced by an aortocaval fistula, dual inhibition of ETA and ETB prevented mast cell degranulation and the associated increase in cardiac MMP levels, interstitial collagen degradation, and ventricular dilatation [153]. On the other hand, dual inhibition of ETA and ETB in a rat model of RIHD did not alter radiation-induced functional or structural cardiac changes [97]. Moreover, selective ETA inhibition led to an increase in the number of sclerotic vessels in a rat model of localized intestine irradiation [154]. Dosing of receptor antagonists and opposing cardiovascular effects of the ETA and ETB receptors [155, 156] warrant further studies to clarify the role of ET-1 and its two receptors in RIHD.

CONCLUSIONS: CLUES TO POSSIBLE DRUG TARGETS

Experimental models of local heart irradiation have shed light on the pathogenesis of RIHD. Modifiers of endothelial injury, TGF-β, RAS, cardiac sensory nerves, and the endothelin system may potentially modify manifestations of RIHD. Nevertheless, many mechanisms of this disease may still be unknown.

ACKNOWLEDGEMENTS

This work was supported in part by the National Institutes of Health (CA71382 and CA83719 to MH-J), the American Heart Association (AHA 0425933 to MB) and the Lance Armstrong Foundation (LAF06SY4 to MB). We also thank the Office of Grants and Scientific Publications at the University of Arkansas for Medical Sciences for editorial assistance in the preparation of the manuscript.

ABBREVIATIONS

ACE

Angiotensin converting enzyme

AngII

Angiotensin II

CGRP

Calcitonin gene related peptide

ET-1

Endothelin-1

IGF-1

Insulin-like growth factor-1

MMP

Metalloproteinase

MRI

Magnetic resonance imaging

PET

Positron emission tomography

RAS

Renin-angiotensin system

RIHD

Radiation-induced heart disease

SPECT

Single photon emission computed tomography

TGF-β

Transforming growth factor-beta

TNF-α

Tumor necrosis factor-alpha

Ws

White spotting gene

REFERENCES

  • 1.Verdecchia A, Guzzinati S, Francisci S, et al. Survival trends in European cancer patients diagnosed from 1988 to 1999. Eur J Cancer. 2009;45:1042–1066. doi: 10.1016/j.ejca.2008.11.029. [DOI] [PubMed] [Google Scholar]
  • 2.Gatta G, Zigon G, Capocaccia R, et al. Survival of European children and young adults with cancer diagnosed 1995–2002. Eur J Cancer. 2009;45:992–1005. doi: 10.1016/j.ejca.2008.11.042. [DOI] [PubMed] [Google Scholar]
  • 3.Adams MJ, Hardenbergh PH, Constine LS, et al. Radiation-associated cardiovascular disease. Crit Rev Oncol Hematol. 2003;45:55–75. doi: 10.1016/s1040-8428(01)00227-x. [DOI] [PubMed] [Google Scholar]
  • 4.Heidenreich PA, Hancock SL, Vagelos RH, et al. Diastolic dysfunction after mediastinal irradiation. Am Heart J. 2005;150:977–982. doi: 10.1016/j.ahj.2004.12.026. [DOI] [PubMed] [Google Scholar]
  • 5.Senkus-Konefka E, Jassem J. Cardiovascular effects of breast cancer radiotherapy. Cancer Treat Rev. 2007;33:578–593. doi: 10.1016/j.ctrv.2007.07.011. [DOI] [PubMed] [Google Scholar]
  • 6.Taylor CW, McGale P, Darby SC. Cardiac risks of breast-cancer radiotherapy: a contemporary view. Clin Oncol (R Coll Radiol) 2006;18:236–246. doi: 10.1016/j.clon.2005.11.003. [DOI] [PubMed] [Google Scholar]
  • 7.Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al. Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol. 2003;21:3431–3439. doi: 10.1200/JCO.2003.07.131. [DOI] [PubMed] [Google Scholar]
  • 8.Hooning MJ, Aleman BM, van Rosmalen AJ, et al. Cause-specific mortality in long-term survivors of breast cancer: A 25-year follow-up study. Int J Radiat Oncol Biol Phys. 2006;64:1081–1091. doi: 10.1016/j.ijrobp.2005.10.022. [DOI] [PubMed] [Google Scholar]
  • 9.Gyenes G, Rutqvist LE, Liedberg A, et al. Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer. Radiother Oncol. 1998;48:185–190. doi: 10.1016/s0167-8140(98)00062-0. [DOI] [PubMed] [Google Scholar]
  • 10.Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994;12:447–453. doi: 10.1200/JCO.1994.12.3.447. [DOI] [PubMed] [Google Scholar]
  • 11.Early Breast Cancer Trialists Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet. 2000;355:1757–1770. [PubMed] [Google Scholar]
  • 12.Borger JH, Hooning MJ, Boersma LJ, et al. Cardiotoxic effects of tangential breast irradiation in early breast cancer patients: the role of irradiated heart volume. Int J Radiat Oncol Biol Phys. 2007;69:1131–1138. doi: 10.1016/j.ijrobp.2007.04.042. [DOI] [PubMed] [Google Scholar]
  • 13.Darby SC, McGale P, Taylor CW, et al. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 2005;6:557–565. doi: 10.1016/S1470-2045(05)70251-5. [DOI] [PubMed] [Google Scholar]
  • 14.Chera BS, Rodriguez C, Morris CG, et al. Dosimetric comparison of three different involved nodal irradiation techniques for stage II hodgkin's lymphoma patients: conventional radiotherapy, intensity-modulated radiotherapy, and three-dimensional proton radiotherapy. Int J Radiat Oncol Biol Phys. 2009;75:1173–1180. doi: 10.1016/j.ijrobp.2008.12.048. [DOI] [PubMed] [Google Scholar]
  • 15.Tillman GF, Pawlicki T, Koong AC, et al. Preoperative versus postoperative radiotherapy for locally advanced gastroesophageal junction and proximal gastric cancers: a comparison of normal tissue radiation doses. Dis Esophagus. 2008;21:437–444. doi: 10.1111/j.1442-2050.2007.00794.x. [DOI] [PubMed] [Google Scholar]
  • 16.Weber DC, Peguret N, Dipasquale G, et al. Involved-Node and Involved-Field Volumetric Modulated Arc vs Fixed Beam Intensity-Modulated Radiotherapy for Female Patients with Early-Stage Supra-Diaphragmatic Hodgkin Lymphoma: A Comparative Planning Study. Int J Radiat Oncol Biol Phys. 2009;75:1578–1586. doi: 10.1016/j.ijrobp.2009.05.012. [DOI] [PubMed] [Google Scholar]
  • 17.Hong TS, Crowley EM, Killoran J, et al. Considerations in treatment planning for esophageal cancer. Semin Radiat Oncol. 2007;17:53–61. doi: 10.1016/j.semradonc.2006.09.001. [DOI] [PubMed] [Google Scholar]
  • 18.Wu WC, Chan CL, Wong YW, et al. A study on the influence of breathing phases in intensity-modulated radiotherapy of lung tumours using four-dimensional CT. Br J Radiol. 2010;83:252–256. doi: 10.1259/bjr/33094251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Zhang X, Li Y, Pan X, et al. Intensity-Modulated Proton Therapy Reduces the Dose to Normal Tissue Compared with Intensity-Modulated Radiation Therapy or Passive Scattering Proton Therapy and Enables Individualized Radical Radiotherapy for Extensive Stage IIIB Non-Small-Cell Lung Cancer: A Virtual Clinical Study. Int J Radiat Oncol Biol Phys. 2010;77:357–366. doi: 10.1016/j.ijrobp.2009.04.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.McGale P, Darby SC. Low doses of ionizing radiation and circulatory diseases: a systematic review of the published epidemiological evidence. Radiat Res. 2005;163:247–257. doi: 10.1667/rr3314. [DOI] [PubMed] [Google Scholar]
  • 21.Taylor CW, Povall JM, McGale P, et al. Cardiac dose from tangential breast cancer radiotherapy in the year 2006. Int J Radiat Oncol Biol Phys. 2008;72:501–507. doi: 10.1016/j.ijrobp.2007.12.058. [DOI] [PubMed] [Google Scholar]
  • 22.Demirci S, Nam J, Hubbs JL, et al. Radiation-induced cardiac toxicity after therapy for breast cancer: interaction between treatment era and follow-up duration. Int J Radiat Oncol Biol Phys. 2009;73:980–987. doi: 10.1016/j.ijrobp.2008.11.016. [DOI] [PubMed] [Google Scholar]
  • 23.Hardenbergh PH, Munley MT, Bentel GC, et al. Cardiac perfusion changes in patients treated for breast cancer with radiation therapy and doxorubicin: preliminary results. Int J Radiat Oncol Biol Phys. 2001;49:1023–1028. doi: 10.1016/s0360-3016(00)01531-5. [DOI] [PubMed] [Google Scholar]
  • 24.Prosnitz RG, Hubbs JL, Evans ES, et al. Prospective assessment of radiotherapy-associated cardiac toxicity in breast cancer patients: analysis of data 3 to 6 years after treatment. Cancer. 2007;110:1840–1850. doi: 10.1002/cncr.22965. [DOI] [PubMed] [Google Scholar]
  • 25.Seddon B, Cook A, Gothard L, et al. Detection of defects in myocardial perfusion imaging in patients with early breast cancer treated with radiotherapy. Radiother Oncol. 2002;64:53–63. doi: 10.1016/s0167-8140(02)00133-0. [DOI] [PubMed] [Google Scholar]
  • 26.McChesney SL, Gillette EL, Powers BE. Radiation-induced cardiomyopathy in the dog. Radiat Res. 1988;113:120–132. [PubMed] [Google Scholar]
  • 27.Schultz-Hector S, Balz K. Radiation-induced loss of endothelial alkaline phosphatase activity and development of myocardial degeneration. An ultrastructural study. Lab Investig. 1994;71:252–260. [PubMed] [Google Scholar]
  • 28.Yang VV, Stearner SP, Tyler SA. Radiation-induced changes in the fine structure of the heart: comparison of fission neutrons and 60Co gamma rays in the mouse. Radiat Res. 1976;67:344–360. [PubMed] [Google Scholar]
  • 29.Eltringham JR, Fajardo LF, Stewart JR. Adriamycin cardiomyopathy: enhanced cardiac damage in rabbits with combined drug and cardiac irradiation. Radiology. 1975;115:471–472. doi: 10.1148/115.2.471. [DOI] [PubMed] [Google Scholar]
  • 30.Labudova O, Hardmeier R, Rink H, et al. The transcription of the XRCC1 gene in the heart of radiation-resistant and radiation-sensitive mice after ionizing irradiation. Pediatr Res. 1997;41:435–439. doi: 10.1203/00006450-199703000-00022. [DOI] [PubMed] [Google Scholar]
  • 31.Schultz-Hector S, Trott KR. Radiation-induced cardiovascular diseases: Is the epidemiologic evidence compatible with the radiobiologic data? Int J Radiat Oncol Biol Phys. 2007;67:10–18. doi: 10.1016/j.ijrobp.2006.08.071. [DOI] [PubMed] [Google Scholar]
  • 32.Hoving S, Heeneman S, Gijbels MJ, et al. Single-dose and fractionated irradiation promote initiation and progression of atherosclerosis and induce an inflammatory plaque phenotype in ApoE(−/−) mice. Int J Radiat Oncol Biol Phys. 2008;71:848–857. doi: 10.1016/j.ijrobp.2008.02.031. [DOI] [PubMed] [Google Scholar]
  • 33.Stewart FA, Heeneman S, Te PJ, et al. Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE−/− mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage. Am J Pathol. 2006;168:649–658. doi: 10.2353/ajpath.2006.050409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Lauk S, Trott KR. Radiation induced heart disease in hypertensive rats. Int J Radiat Oncol Biol Phys. 1988;14:109–114. doi: 10.1016/0360-3016(88)90058-2. [DOI] [PubMed] [Google Scholar]
  • 35.Gold H. Atherosclerosis in the rat. Effect of x-ray and a high fat diet. Proc Soc Exper Biol Med. 1962;111:593–595. doi: 10.3181/00379727-111-27865. [DOI] [PubMed] [Google Scholar]
  • 36.Kitahara T, Liu K, Solanki K, et al. Functional and morphological damage after local heart irradiation and/or adriamycin in Wistar rats. Radiat Oncol Investig. 1993;1:198–205. [Google Scholar]
  • 37.Kruse JJ, Zurcher C, Strootman EG, et al. Structural changes in the auricles of the rat heart after local ionizing irradiation. Radiother Oncol. 2001;58:303–311. doi: 10.1016/s0167-8140(00)00327-3. [DOI] [PubMed] [Google Scholar]
  • 38.Lauk S, Kiszel Z, Buschmann J, et al. Radiation-induced heart disease in rats. Int J Radiat Oncol Biol Phys. 1985;11:801–808. doi: 10.1016/0360-3016(85)90314-1. [DOI] [PubMed] [Google Scholar]
  • 39.Hu S, Chen Y, Li L, et al. Effects of adenovirus-mediated delivery of the human hepatocyte growth factor gene in experimental radiation-induced heart disease. Int J Radiat Oncol Biol Phys. 2009;75:1537–1544. doi: 10.1016/j.ijrobp.2009.07.1697. [DOI] [PubMed] [Google Scholar]
  • 40.Franken NA, Camps JA, Van Ravels FJ, et al. Comparison of in vivo cardiac function with ex vivo cardiac performance of the rat heart after thoracic irradiation. Br J Radiol. 1997;70:1004–1009. doi: 10.1259/bjr.70.838.9404203. [DOI] [PubMed] [Google Scholar]
  • 41.Wondergem J, van der Laarse A, Van Ravels FJ, et al. In vitro assessment of cardiac performance after irradiation using an isolated working rat heart preparation. Int J Radiat Biol. 1991;59:1053–1068. doi: 10.1080/09553009114550931. [DOI] [PubMed] [Google Scholar]
  • 42.Boerma M, Wang J, Wondergem J, et al. Influence of mast cells on structural and functional manifestations of radiation-induced heart disease. Cancer Res. 2005;65:3100–3107. doi: 10.1158/0008-5472.CAN-04-4333. [DOI] [PubMed] [Google Scholar]
  • 43.Veinot JP, Edwards WD. Pathology of radiation-induced heart disease: a surgical and autopsy study of 27 cases. Hum Pathol. 1996;27:766–773. doi: 10.1016/s0046-8177(96)90447-5. [DOI] [PubMed] [Google Scholar]
  • 44.Brosius FC, Waller BF, Roberts WC. Radiation heart disease. Analysis of 16 young (aged 15 to 33 years) necropsy patients who received over 3,500 rads to the heart. Am J Med. 1981;70:519–530. doi: 10.1016/0002-9343(81)90574-x. [DOI] [PubMed] [Google Scholar]
  • 45.Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors of Hodgkin's disease treated with chest radiotherapy. J Clin Oncol. 2004;22:3139–3148. doi: 10.1200/JCO.2004.09.109. [DOI] [PubMed] [Google Scholar]
  • 46.Hamza A, Tunick PA, Kronzon I. Echocardiographic manifestations of complications of radiation therapy. Echocardiography. 2009;26:724–728. doi: 10.1111/j.1540-8175.2008.00878.x. [DOI] [PubMed] [Google Scholar]
  • 47.Schultz-Hector S. Radiation-induced heart disease: review of experimental data on dose response and pathogenesis. Int J Radiat Biol. 1992;61:149–160. doi: 10.1080/09553009214550761. [DOI] [PubMed] [Google Scholar]
  • 48.Wang J, Boerma M, Fu Q, et al. Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy. World J Gastroenterol. 2007;13:3047–3055. doi: 10.3748/wjg.v13.i22.3047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Hopewell JW, Calvo W, Jaenke R, et al. Microvasculature and radiation damage. Recent Results Cancer Res. 1993;130:1–16. doi: 10.1007/978-3-642-84892-6_1. [DOI] [PubMed] [Google Scholar]
  • 50.Fajardo LF, Stewart JR. Capillary injury preceding radiation-induced myocardial fibrosis. Radiology. 1971;101:429–433. doi: 10.1148/101.2.429. [DOI] [PubMed] [Google Scholar]
  • 51.Lauk S, Trott KR. Endothelial cell proliferation in the rat heart following local heart irradiation. Int J Radiat Biol. 1990;57:1017–1030. doi: 10.1080/09553009014551131. [DOI] [PubMed] [Google Scholar]
  • 52.Boerma M, Kruse JJ, van L, et al. Increased deposition of von Willebrand factor in the rat heart after local ionizing irradiation. Strahlenther Onkol. 2004;180:109–116. doi: 10.1007/s00066-004-1138-0. [DOI] [PubMed] [Google Scholar]
  • 53.Baker JE, Fish BL, Su J, et al. 10 Gy total body irradiation increases risk of coronary sclerosis, degeneration of heart structure and function in a rat model. Int J Radiat Biol. 2009;85:1089–1100. doi: 10.3109/09553000903264473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007;74:184–195. doi: 10.1016/j.cardiores.2006.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Lim H, Zhu YZ. Role of transforming growth factor-beta in the progression of heart failure. Cell Mol Life Sci. 2006;63:2584–2596. doi: 10.1007/s00018-006-6085-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Rodemann HP, Binder A, Burger A, et al. The underlying cellular mechanism of fibrosis. Kidney Int Suppl. 1996;54:S32–S36. [PubMed] [Google Scholar]
  • 57.Richter KK, Langberg CW, Sung CC, et al. Association of transforming growth factor beta (TGF-beta) immunoreactivity with specific histopathologic lesions in subacute and chronic experimental radiation enteropathy. Radiother Oncol. 1996;39:243–251. doi: 10.1016/0167-8140(95)01735-6. [DOI] [PubMed] [Google Scholar]
  • 58.Barcellos-Hoff MH. How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues. Radiat Res. 1998;150:S109–S120. [PubMed] [Google Scholar]
  • 59.Scharpfenecker M, Floot B, Russell NS, et al. Endoglin haploinsufficiency reduces radiation-induced fibrosis and telangiectasia formation in mouse kidneys. Radiother Oncol. 2009;92:484–491. doi: 10.1016/j.radonc.2009.06.013. [DOI] [PubMed] [Google Scholar]
  • 60.Kruse JJ, Floot BG, te Poele JA, et al. Radiation-induced activation of TGF-beta signaling pathways in relation to vascular damage in mouse kidneys. Radiat Res. 2009;171:188–197. doi: 10.1667/RR1526.1. [DOI] [PubMed] [Google Scholar]
  • 61.Boerma M, Roberto KA, Hauer-Jensen M. Prevention and treatment of functional and structural radiation injury in the rat heart by pentoxifylline and alpha-tocopherol. Int J Radiat Oncol Biol Phys. 2008;72:170–177. doi: 10.1016/j.ijrobp.2008.04.042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Kruse JJ, Bart CI, Visser A, et al. Changes in transforming growth factor-beta (TGF-beta1), procollagen types I and III mRNA in the rat heart after irradiation. Int J Radiat Biol. 1999;75:1429–1436. doi: 10.1080/095530099139296. [DOI] [PubMed] [Google Scholar]
  • 63.Liu H, Xiong M, Xia YF, et al. Studies on pentoxifylline and tocopherol combination for radiation-induced heart disease in rats. Int J Radiat Oncol Biol Phys. 2009;73:1552–1559. doi: 10.1016/j.ijrobp.2008.12.005. [DOI] [PubMed] [Google Scholar]
  • 64.Fyhrquist F, Saijonmaa O. Renin-angiotensin system revisited. J Intern Med. 2008;264:224–236. doi: 10.1111/j.1365-2796.2008.01981.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Ferrario CM. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J Renin Ang Syst. 2006;7:3–14. doi: 10.3317/jraas.2006.003. [DOI] [PubMed] [Google Scholar]
  • 66.Balcells E, Meng QC, Johnson WHJ, et al. Angiotensin II formation from ACE and chymase in human and animal hearts: methods and species considerations. Am J Physiol. 1997;273:H1769–H1774. doi: 10.1152/ajpheart.1997.273.4.H1769. [DOI] [PubMed] [Google Scholar]
  • 67.Sciarretta S, Paneni F, Palano F, et al. Role of the reninangiotensin-aldosterone system and inflammatory processes in the development and progression of diastolic dysfunction. Clin Sci (Lond) 2009;116:467–477. doi: 10.1042/CS20080390. [DOI] [PubMed] [Google Scholar]
  • 68.Miyazaki M, Takai S. Tissue angiotensin II generating system by angiotensin-converting enzyme and chymase. J Pharmacol Sci. 2006;100:391–397. doi: 10.1254/jphs.cpj06008x. [DOI] [PubMed] [Google Scholar]
  • 69.Lundequist A, Tchougounova E, Abrink M, et al. Cooperation between mast cell carboxypeptidase A and the chymase mouse mast cell protease 4 in the formation and degradation of angiotensin II. J Biol Chem. 2004;279:32339–32344. doi: 10.1074/jbc.M405576200. [DOI] [PubMed] [Google Scholar]
  • 70.Bader M. Role of the local renin-angiotensin system in cardiac damage: a minireview focussing on transgenic animal models. J Mol Cell Cardiol. 2002;34:1455–1462. doi: 10.1006/jmcc.2002.2077. [DOI] [PubMed] [Google Scholar]
  • 71.Xiao HD, Fuchs S, Bernstein EA, et al. Mice expressing ACE only in the heart show that increased cardiac angiotensin II is not associated with cardiac hypertrophy. Am J Physiol Heart Circ Physiol. 2008;294:H659–H667. doi: 10.1152/ajpheart.01147.2007. [DOI] [PubMed] [Google Scholar]
  • 72.Robbins ME, Diz DI. Pathogenic role of the renin-angiotensin system in modulating radiation-induced late effects. Int J Radiat Oncol Biol Phys. 2006;64:6–12. doi: 10.1016/j.ijrobp.2005.08.033. [DOI] [PubMed] [Google Scholar]
  • 73.Moulder JE, Fish BL, Cohen EP. Treatment of radiation nephropathy with ACE inhibitors and AII type-1 and type-2 receptor antagonists. Curr Pharm Des. 2007;13:1317–1325. doi: 10.2174/138161207780618821. [DOI] [PubMed] [Google Scholar]
  • 74.Robbins ME, Payne V, Tommasi E, et al. The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys. 2009;73:499–505. doi: 10.1016/j.ijrobp.2008.09.058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Molteni A, Moulder JE, Cohen EF, et al. Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker. International Journal of Radiation Biology. 2000;76:523–532. doi: 10.1080/095530000138538. [DOI] [PubMed] [Google Scholar]
  • 76.Moulder JE, Fish BL, Cohen EP. Angiotensin II receptor antagonists in the treatment and prevention of radiation nephropathy. Int J Radiat Biol. 1998;73:415–421. doi: 10.1080/095530098142257. [DOI] [PubMed] [Google Scholar]
  • 77.Wu R, Zeng Y. Does angiotensin II-aldosterone have a role in radiation-induced heart disease? Med Hypotheses. 2008;72:263–266. doi: 10.1016/j.mehy.2008.09.051. [DOI] [PubMed] [Google Scholar]
  • 78.Molteni A, Wolfe LF, Ward WF, et al. Effect of an angiotensin II receptor blocker and two angiotensin converting enzyme inhibitors on transforming growth factor-beta (TGF-beta) and alpha-actomyosin (alpha SMA), important mediators of radiation-induced pneumopathy and lung fibrosis. Curr Pharm Des. 2007;13:1307–1316. doi: 10.2174/138161207780618777. [DOI] [PubMed] [Google Scholar]
  • 79.Ward WF, Molteni A, Ts'ao C, et al. The effect of Captopril on benign and malignant reactions in irradiated rat skin. Br J Radiol. 1990;63:349–354. doi: 10.1259/0007-1285-63-749-349. [DOI] [PubMed] [Google Scholar]
  • 80.Yarom R, Harper IS, Wynchank S, et al. Effect of captopril on changes in rats' hearts induced by long-term irradiation. Radiat Res. 1993;133:187–197. [PubMed] [Google Scholar]
  • 81.Galli SJ, Kalesnikoff J, Grimbaldeston MA, et al. Mast cells as "tunable" effector and immunoregulatory cells: recent advances. Annu Rev Immunol. 2005;23:749–786. doi: 10.1146/annurev.immunol.21.120601.141025. [DOI] [PubMed] [Google Scholar]
  • 82.Koskinen PK, Kovanen PT, Lindstedt KA, et al. Mast cells in acute and chronic rejection of rat cardiac allografts--a major source of basic fibroblast growth factor. Transplantation. 2001;71:1741–1747. doi: 10.1097/00007890-200106270-00007. [DOI] [PubMed] [Google Scholar]
  • 83.Li QY, Raza-Ahmad A, MacAulay MA, et al. The relationship of mast cells and their secreted products to the volume of fibrosis in posttransplant hearts. Transplantation. 1992;53:1047–1051. doi: 10.1097/00007890-199205000-00015. [DOI] [PubMed] [Google Scholar]
  • 84.Engels W, Reiters PH, Daemen MJ, et al. Transmural changes in mast cell density in rat heart after infarct induction in vivo. J Pathol. 1995;177:423–429. doi: 10.1002/path.1711770414. [DOI] [PubMed] [Google Scholar]
  • 85.Boerma M, Zurcher C, Esveldt I, et al. Histopathology of ventricles, coronary arteries and mast cell accumulation in transverse and longitudinal sections of the rat heart after irradiation. Oncol Reports. 2004;12:213–219. doi: 10.3892/or.12.2.213. [DOI] [PubMed] [Google Scholar]
  • 86.Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat Immunol. 2008;9:1215–1223. doi: 10.1038/ni.f.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Galli SJ, Tsai M. Mast cells: versatile regulators of inflammation, tissue remodeling, host defense and homeostasis. J Dermatol Sci. 2008;49:7–19. doi: 10.1016/j.jdermsci.2007.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Geissler EN, Russell ES. Analysis of the hematopoietic effects of new dominant spotting (W) mutations of the mouse. II. Effects on mast cell development. Exp Hematol. 1983;11:461–466. [PubMed] [Google Scholar]
  • 89.Kitamura Y, Go S. Decreased production of mast cells in S1/S1d anemic mice. Blood. 1979;53:492–497. [PubMed] [Google Scholar]
  • 90.Kitamura Y, Go S, Hatanaka K. Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood. 1978;52:447–452. [PubMed] [Google Scholar]
  • 91.Tsujimura T, Hirota S, Nomura S, et al. Characterization of Ws mutant allele of rats: a 12-base deletion in tyrosine kinase domain of c-kit gene. Blood. 1991;78:1942–1946. [PubMed] [Google Scholar]
  • 92.Horiguchi K, Komuro T. Ultrastructural characterization of interstitial cells of Cajal in the rat small intestine using control and Ws/Ws mutant rats. Cell Tissue Res. 1998;293:277–284. doi: 10.1007/s004410051119. [DOI] [PubMed] [Google Scholar]
  • 93.Morimoto M, Kasugai T, Tei H, et al. Age-dependent amelioration of hypoplastic anemia in Ws/Ws rats with a small deletion at the kinase domain of c-kit. Blood. 1993;82:3315–3320. [PubMed] [Google Scholar]
  • 94.Niwa Y, Kasugai T, Ohno K, et al. Anemia and mast cell depletion in mutant rats that are homozygous at "white spotting (Ws)" locus. Blood. 1991;78:1936–1941. [PubMed] [Google Scholar]
  • 95.Boerma M, Fiser WP, Hoyt G, et al. Influence of mast cells on outcome after heterotopic cardiac transplantation in rats. Transpl Int. 2007;20:256–265. doi: 10.1111/j.1432-2277.2006.00420.x. [DOI] [PubMed] [Google Scholar]
  • 96.Joseph J, Kennedy RH, Devi S, et al. Protective role of mast cells in homocysteine-induced cardiac remodeling. Am J Physiol Heart Circ Physiol. 2005;288:H2541–H2545. doi: 10.1152/ajpheart.00806.2004. [DOI] [PubMed] [Google Scholar]
  • 97.Boerma M, Wang J, Kulkarni A, et al. Influence of endothelin-1 receptor inhibition on functional, structural and molecular changes in the rat heart after irradiation. Radiat Res. 2008;170:275–283. doi: 10.1667/RR1093.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Williams RM, Bienenstock J, Stead RH. Mast cells: the neuroimmune connection. Chem Immunol. 1995;61:208–235. [PubMed] [Google Scholar]
  • 99.Arizono N, Matsuda S, Hattori T, et al. Anatomical variation in mast cell nerve associations in the rat small intestine, heart, lung, and skin. Similarities of distances between neural processes and mast cells, eosinophils, or plasma cells in the jejunal lamina propria. Lab Invest. 1990;62:626–634. [PubMed] [Google Scholar]
  • 100.Laine P, Naukkarinen A, Heikkila L, et al. Adventitial mast cells connect with sensory nerve fibers in atherosclerotic coronary arteries. Circulation. 2000;101:1665–1669. doi: 10.1161/01.cir.101.14.1665. [DOI] [PubMed] [Google Scholar]
  • 101.Ito A, Oonuma J. Direct interaction between nerves and mast cells mediated by the SgIGSF/SynCAM adhesion molecule. J Pharmacol Sci. 2006;102:1–5. doi: 10.1254/jphs.cpj06014x. [DOI] [PubMed] [Google Scholar]
  • 102.Skaper SD, Pollock M, Facci L. Mast cells differentially express and release active high molecular weight neurotrophins. Brain Res Mol Brain Res. 2001;97:177–185. doi: 10.1016/s0169-328x(01)00314-x. [DOI] [PubMed] [Google Scholar]
  • 103.Schulze W, Fu ML. Localization of alpha 1-adrenoceptors in rat and human hearts by immunocytochemistry. Mol Cell Biochem. 1996;163–164:159–165. doi: 10.1007/BF00408653. [DOI] [PubMed] [Google Scholar]
  • 104.Kay LJ, Peachell PT. Mast cell beta2-adrenoceptors. Chem Immunol Allergy. 2005;87:145–153. doi: 10.1159/000087641. [DOI] [PubMed] [Google Scholar]
  • 105.Facoetti A, Fallarini S, Miserere S, et al. Histochemical study of cardiac mast cells degranulation and collagen deposition: interaction with the cathecolaminergic system in the rat. Eur J Histochem. 2006;50:133–140. [PubMed] [Google Scholar]
  • 106.Reynier-Rebuffel AM, Mathiau P, Callebert J, et al. Substance P, calcitonin gene-related peptide, and capsaicin release serotonin from cerebrovascular mast cells. Am J Physiol. 1994;267:R1421–R1429. doi: 10.1152/ajpregu.1994.267.5.R1421. [DOI] [PubMed] [Google Scholar]
  • 107.Shen GH, Grundemar L, Zukowska-Grojec Z, et al. C-terminal neuropeptide Y fragments are mast cell-dependent vasodepressor agents. Eur J Pharmacol. 1991;204:249–256. doi: 10.1016/0014-2999(91)90849-l. [DOI] [PubMed] [Google Scholar]
  • 108.Grundemar L, Wahlestedt C, Shen GH, et al. Biphasic blood pressure response to neuropeptide Y in anesthetized rats. Eur J Pharmacol. 1990;179:83–87. doi: 10.1016/0014-2999(90)90404-t. [DOI] [PubMed] [Google Scholar]
  • 109.Arzubiaga C, Morrow J, Roberts LJ, et al. Neuropeptide Y, a putative cotransmitter in noradrenergic neurons, induces mast cell degranulation but not prostaglandin D2 release. J Allergy Clin Immunol. 1991;87:88–93. doi: 10.1016/0091-6749(91)90216-b. [DOI] [PubMed] [Google Scholar]
  • 110.Moriyama M, Sato T, Inoue H, et al. The neuropeptide neuromedin U promotes inflammation by direct activation of mast cells. J Exp Med. 2005;202:217–224. doi: 10.1084/jem.20050248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.Morgan LG, Levick SP, Voloshneyuk TG, et al. A novel technique for isolating functional mast cells from the heart. Inflam Res. 2008;57:241–246. doi: 10.1007/s00011-007-7059-5. [DOI] [PubMed] [Google Scholar]
  • 112.Hua XY, Back SM, Tam EK. Substance P enhances electrical field stimulation-induced mast cell degranulation in rat trachea. Am J Physiol. 1996;270:L985–L991. doi: 10.1152/ajplung.1996.270.6.L985. [DOI] [PubMed] [Google Scholar]
  • 113.Janiszewski J, Bienenstock J, Blennerhassett MG. Picomolar doses of substance P trigger electrical responses in mast cells without degranulation. Am J Physiol. 1994;267:C138–C145. doi: 10.1152/ajpcell.1994.267.1.C138. [DOI] [PubMed] [Google Scholar]
  • 114.Saavedra Y, Vergara P. Somatostatin inhibits intestinal mucosal mast cell degranulation in normal conditions and during mast cell hyperplasia. Regul Pept. 2003;111:67–75. doi: 10.1016/s0167-0115(02)00254-9. [DOI] [PubMed] [Google Scholar]
  • 115.Tuncel N, Tore F, Sahinturk V, et al. Vasoactive intestinal peptide inhibits degranulation and changes granular content of mast cells: a potential therapeutic strategy in controlling septic shock. Peptides. 2000;21:81–89. doi: 10.1016/s0196-9781(99)00177-1. [DOI] [PubMed] [Google Scholar]
  • 116.Leon A, Buriani A, Dal TR, et al. Mast cells synthesize, store, and release nerve growth factor. Proc Natl Acad Sci USA. 1994;91:3739–3743. doi: 10.1073/pnas.91.9.3739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117.Ieda M, Kanazawa H, Ieda Y, et al. Nerve growth factor is critical for cardiac sensory innervation and rescues neuropathy in diabetic hearts. Circulation. 2006;114:2351–2363. doi: 10.1161/CIRCULATIONAHA.106.627588. [DOI] [PubMed] [Google Scholar]
  • 118.Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci. 2001;24:1217–1281. doi: 10.1146/annurev.neuro.24.1.1217. [DOI] [PubMed] [Google Scholar]
  • 119.Corvera CU, Dery O, McConalogue K, et al. Thrombin and mast cell tryptase regulate guinea-pig myenteric neurons through proteinase-activated receptors-1 and -2. J Physiol. 1999;517:741–756. doi: 10.1111/j.1469-7793.1999.0741s.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 120.Saito T, Bunnett NW. Protease-activated receptors: regulation of neuronal function. Neuromol Med. 2005;7:79–99. doi: 10.1385/NMM:7:1-2:079. [DOI] [PubMed] [Google Scholar]
  • 121.Fuder H, Ries P, Schwarz P. Histamine and serotonin released from the rat perfused heart by compound 48/80 or by allergen challenge influence noradrenaline or acetylcholine exocytotic release. Fundam Clin Pharmacol. 1994;8:477–490. doi: 10.1111/j.1472-8206.1994.tb00829.x. [DOI] [PubMed] [Google Scholar]
  • 122.Tam EK, Caughey GH. Degradation of airway neuropeptides by human lung tryptase. Am J Respir Cell Mol Biol. 1990;3:27–32. doi: 10.1165/ajrcmb/3.1.27. [DOI] [PubMed] [Google Scholar]
  • 123.Caughey GH, Raymond WW, Wolters PJ. Angiotensin II generation by mast cell alpha- and beta-chymases. Biochim Biophys Acta. 2000;1480:245–257. doi: 10.1016/s0167-4838(00)00076-5. [DOI] [PubMed] [Google Scholar]
  • 124.Walls AF, Brain SD, Desai A, et al. Human mast cell tryptase attenuates the vasodilator activity of calcitonin gene-related peptide. Biochem Pharmacol. 1992;43:1243–1248. doi: 10.1016/0006-2952(92)90498-8. [DOI] [PubMed] [Google Scholar]
  • 125.Nesto RW, Phillips RT. Asymptomatic myocardial ischemia in diabetic patients. Am J Med. 1986;80:40–47. doi: 10.1016/0002-9343(86)90451-1. [DOI] [PubMed] [Google Scholar]
  • 126.Aring AM, Jones DE, Falko JM. Evaluation and prevention of diabetic neuropathy. Am Fam Physician. 2005;71:2123–2128. [PubMed] [Google Scholar]
  • 127.Csont T, Csonka C, Kovacs P, et al. Capsaicin-sensitive sensory neurons regulate myocardial nitric oxide and cGMP signaling. Eur J Pharmacol. 2003;476:107–113. doi: 10.1016/s0014-2999(03)02117-4. [DOI] [PubMed] [Google Scholar]
  • 128.Preibisz JJ. Calcitonin gene-related peptide and regulation of human cardiovascular homeostasis. Am J Hypertens. 1993;6:434–450. doi: 10.1093/ajh/6.5.434. [DOI] [PubMed] [Google Scholar]
  • 129.Harada N, Okajima K. Effect of capsaicin on plasma and tissue levels of insulin-like growth factor-I in spontaneously hypertensive rats. Growth Horm IGF Res. 2008;18:75–81. doi: 10.1016/j.ghir.2007.06.004. [DOI] [PubMed] [Google Scholar]
  • 130.Peng J, Xiao J, Ye F, et al. Inhibition of cardiac tumor necrosis factor-alpha production by calcitonin gene-related peptide-mediated ischemic preconditioning in isolated rat hearts. Eur J Pharmacol. 2000;407:303–308. doi: 10.1016/s0014-2999(00)00702-0. [DOI] [PubMed] [Google Scholar]
  • 131.Li YJ, Peng J. The cardioprotection of calcitonin gene-related peptide-mediated preconditioning. Eur J Pharmacol. 2002;442:173–177. doi: 10.1016/s0014-2999(02)01538-8. [DOI] [PubMed] [Google Scholar]
  • 132.Katona M, Boros K, Santha P, et al. Selective sensory denervation by capsaicin aggravates adriamycin-induced cardiomyopathy in rats. Naunyn Schmiedebergs Arch Pharmacol. 2004;370:436–443. doi: 10.1007/s00210-004-0985-7. [DOI] [PubMed] [Google Scholar]
  • 133.Limesand KH, Said S, Anderson SM. Suppression of radiation-induced salivary gland dysfunction by IGF-1. PLoS ONE. 2009;4:e4663. doi: 10.1371/journal.pone.0004663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 134.Huang XW, Yang J, Dragovic AF, et al. Antisense oligonucleotide inhibition of tumor necrosis factor receptor 1 protects the liver from radiation-induced apoptosis. Clin Cancer Res. 2006;12:2849–2855. doi: 10.1158/1078-0432.CCR-06-0360. [DOI] [PubMed] [Google Scholar]
  • 135.Wang J, Qiu X, Kulkarni A, et al. Calcitonin gene-related peptide and substance P regulate the intestinal radiation response. Clin Cancer Res. 2006;12:4112–4118. doi: 10.1158/1078-0432.CCR-06-0592. [DOI] [PubMed] [Google Scholar]
  • 136.Yang LL, Arab S, Liu P, et al. The role of endothelin-1 in myocarditis and inflammatory cardiomyopathy: old lessons and new insights. Can J Physiol Pharmacol. 2005;83:47–62. doi: 10.1139/y05-002. [DOI] [PubMed] [Google Scholar]
  • 137.Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001;41:851–876. doi: 10.1146/annurev.pharmtox.41.1.851. [DOI] [PubMed] [Google Scholar]
  • 138.Simard E, Jin D, Takai S, et al. Chymase-dependent conversion of Big endothelin-1 in the mouse in vivo. J Pharmacol Exp Ther. 2009;328:540–548. doi: 10.1124/jpet.108.142992. [DOI] [PubMed] [Google Scholar]
  • 139.Giannessi D, Del RS, Vitale RL. The role of endothelins and their receptors in heart failure. Pharmacol Res. 2001;43:111–126. doi: 10.1006/phrs.2000.0758. [DOI] [PubMed] [Google Scholar]
  • 140.Cernacek P, Stewart DJ, Monge JC, et al. The endothelin system and its role in acute myocardial infarction. Can J Physiol Pharmacol. 2003;81:598–606. doi: 10.1139/y03-052. [DOI] [PubMed] [Google Scholar]
  • 141.Ertl G, Bauersachs J. Endothelin receptor antagonists in heart failure: current status and future directions. Drugs. 2004;64:1029–1040. doi: 10.2165/00003495-200464100-00001. [DOI] [PubMed] [Google Scholar]
  • 142.Sakai S, Miyauchi T, Sakurai T, et al. Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing heart. Circulation. 1996;93:1214–1222. doi: 10.1161/01.cir.93.6.1214. [DOI] [PubMed] [Google Scholar]
  • 143.Piuhola J, Szokodi I, Kinnunen P, et al. Endothelin-1 contributes to the Frank-Starling response in hypertrophic rat hearts. Hypertension. 2003;41:93–98. doi: 10.1161/01.hyp.0000050929.96979.ec. [DOI] [PubMed] [Google Scholar]
  • 144.Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol. 1999;61:391–415. doi: 10.1146/annurev.physiol.61.1.391. [DOI] [PubMed] [Google Scholar]
  • 145.Ehrenreich H, Burd PR, Rottem M, et al. Endothelins belong to the assortment of mast cell-derived and mast cell-bound cytokines. New Biol. 1992;4:147–156. [PubMed] [Google Scholar]
  • 146.Maurer M, Wedemeyer J, Metz M, et al. Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature. 2004;432:512–516. doi: 10.1038/nature03085. [DOI] [PubMed] [Google Scholar]
  • 147.Metsarinne KP, Vehmaan-Kreula P, Kovanen PT, et al. Activated mast cells increase the level of endothelin-1 mRNA in cocultured endothelial cells and degrade the secreted Peptide. Arterioscler Thromb Vasc Biol. 2002;22:268–273. doi: 10.1161/hq0202.103994. [DOI] [PubMed] [Google Scholar]
  • 148.Schneider LA, Schlenner SM, Feyerabend TB, et al. Molecular mechanism of mast cell mediated innate defense against endothelin and snake venom sarafotoxin. J Exp Med. 2007;204:2629–2639. doi: 10.1084/jem.20071262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 149.Yamamura H, Nabe T, Kohno S, et al. Endothelin-1 induces release of histamine and leukotriene C4 from mouse bone marrow-derived mast cells. Eur J Pharmacol. 1994;257:235–242. doi: 10.1016/0014-2999(94)90134-1. [DOI] [PubMed] [Google Scholar]
  • 150.Janicki JS, Brower GL, Gardner JD, et al. Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload. Cardiovasc Res. 2006;69:657–665. doi: 10.1016/j.cardiores.2005.10.020. [DOI] [PubMed] [Google Scholar]
  • 151.Lundequist A, Abrink M, Pejler G. Mast cell-dependent activation of pro matrix metalloprotease 2: A role for serglycin proteoglycan-dependent mast cell proteases. Biol Chem. 2006;387:1513–1519. doi: 10.1515/BC.2006.189. [DOI] [PubMed] [Google Scholar]
  • 152.Murray DB, Gardner JD, Brower GL, et al. Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in rats. Am J Physiol Heart Circ Physiol. 2004;287:H2295–H2299. doi: 10.1152/ajpheart.00048.2004. [DOI] [PubMed] [Google Scholar]
  • 153.Murray DB, Gardner JD, Brower GL, et al. Effects of Non-Selective Endothelin-1 Receptor Antagonism on Cardiac Mast Cell-Mediated Ventricular Remodeling in Rats. Am J Physiol Heart Circ Physiol. 2008;294:H1251–H1257. doi: 10.1152/ajpheart.00622.2007. [DOI] [PubMed] [Google Scholar]
  • 154.Jullien N, Blirando K, Milliat F, et al. Up-regulation of endothelin type a receptor in human and rat radiation proctitis: preclinical therapeutic approach with endothelin receptor blockade. Int J Radiat Oncol Biol Phys. 2009;74:528–538. doi: 10.1016/j.ijrobp.2008.12.086. [DOI] [PubMed] [Google Scholar]
  • 155.Piuhola J, Makinen M, Szokodi I, et al. Dual role of endothelin-1 via ETA and ETB receptors in regulation of cardiac contractile function in mice. Am J Physiol Heart Circ Physiol. 2003;285:H112–H118. doi: 10.1152/ajpheart.00480.2002. [DOI] [PubMed] [Google Scholar]
  • 156.Clozel M, Gray GA, Breu V, et al. The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun. 1992;186:867–873. doi: 10.1016/0006-291x(92)90826-7. [DOI] [PubMed] [Google Scholar]

RESOURCES