TABLE 4.
Evidence implicating endogenous peroxynitrite formation and/or protein nitration in cardiac and vascular diseases
| Disease/Trigger | Experimental Model | Main Findings | Reference Nos. |
|---|---|---|---|
| Myocardial ischemia reperfusion (I/R) | |||
| Global I/R | Rat heart | Cardiac dysfunction, decreased efficiency of increased O2 utilization, iNOS expression, increased superoxide and myocardial peroxynitrite/nitrotyrosine (NT) formation in hearts subjected to I/R. NOS or MMP inhibitors, superoxide dismutase, glutathione or urate greatly enhance the recovery of contractile function in postischemic hearts and reduced myocardial nitrotyrosine formation. Urate or NOS inhibitor nitro-L- arginine also improves efficiency of O2 utilization. | 385, 429, 740, 781, 816, 1344, 1345, 1398, 1413, 1478 |
| Regional I/R | Rat | Peroxynitrite decomposition catalysts FP-15 and MnTBAP reduce myocardial infarct size and myocyte apoptosis. | 750, 985 |
| I/R associated with acute cardiac transplantation | Rat | Peroxynitrite decomposition catalyst WW85 reduces lipid peroxidation, NT formation, PARP activation in grafts, improves function, and prolongs survival. | 1027 |
| Regional I/R | Dog | Intracoronary administration of L-arginine or infusion of NO donor SNAP during I/R aggravates myocardial stunning following I/R through increased NT formation in the myocardium of dogs, which is improved by NOS inhibition. | 902, 1437, 1438 |
| Regional or repetitive regional I/R | Pig | Increased nitrotyrosine formation and cardiac dysfunction following I/R. Reduction of infarct size, reactive hyperemia, and myocardial NT formation by peroxynitrite decomposition catalyst FP-15. | 48, 100, 573 |
| Cardiopulmonary bypass surgery | Human | Increased plasma NT levels, myocardial NOS expression/activity, and peroxynitrite formation following myocardial I/R during open heart surgery. | 525, 526, 864 |
| Coronary artery disease | Human | Increased NT formation and cardiac dysfunction in hibernating myocardium. | 47 |
| Myocarditis, cardiac allograft rejection, and transplant coronary artery disease | |||
| Coxsackie B3 virus | Mouse | iNOS expression and myocardial NT formation correlates with the damage. | 96 |
| LPBM5 retrovirus (murine AIDS model) | Mouse | Progressive cardiac dysfunction correlated with increased myocardial inflammation and protein nitration. | 201 |
| Porcine cardiac myosin | Mouse, rat | Autoimmune myocarditis characterized by myocardial destruction, inflammation, and increased iNOS expression and nitrotyrosine formation in inflammatory macrophages and in cardiomyocytes, which is attenuated by iNOS inhibitor aminoguanidine. | 38, 616, 1160 |
| Mixture of inflammatory cytokines | Mouse heart | Increased xanthine oxidase- and NADPH oxidase- dependent superoxide production, nitrotyrosine formation, and cardiac dysfunction, which is improved by superoxide and peroxynitrite scavengers iron and FeTPPS. | 384 |
| Mixture of inflammatory cytokines | Rat heart | Increased myocardial peroxynitrite formation and matrix metalloproteinase 2 activation (MMP-2), LV dysfunction. MMP-2 antibody, or inhibitors attenuated the decline in myocardial function. | 428 |
| Intracoronary inflammatory cytokine | Dog | Increased nitrotyrosine formation and sustained cardiac dysfunction, which is prevented by iNOS inhibitor aminoguanidine or superoxide scavenger OPC-6535. | 210, 978 |
| Endotoxin | Rat heart, rat | Enhanced generation of NO and superoxide and peroxynitrite in dysfunctional hearts and aortas from endotoxemic rats. iNOS inhibitor mercaptoethylguanidine and peroxynitrite decomposition catalyst FeTPPS improved contractile function, endotoxin-induced hypotension, and decreased myocardial and aortic NT formation. It also decreased NFκB inhibitory protein IκB degradation and plasma TNF-α, and vascular endothelial cell- leukocyte activation. | 265, 604, 670, 729, 981 |
| Viral myocarditis, septic shock | Human heart | Increased nitrotyrosine immunoreactivity in myocardial specimens with viral myocarditis and sepsis. | 201, 707 |
| Cardiac allograft | iNOS−/− mice heart | iNOS gene deletion improves graft function, attenuated myocardial NT formation and damage. | 1248 |
| Cardiac allograft | Rat heart | Increased iNOS expression and nitrotyrosine formation during cardiac allograft rejection correlates with the damage, and attenuated by iNOS inhibitor or peroxynitrite decomposition catalyst. | 11, 1104 |
| Cardiac allograft, transplant coronary artery disease | Human heart | Increased iNOS expression and nitrotyrosine formation in human coronary arteries of patients with human transplant coronary artery disease and in human cardiac allografts following rejection. | 342, 1027, 1069, 1249, 1371 |
| Heart failure | |||
| Cardiac-specific iNOS overexpression | Mouse | Increased myocardial peroxynitrite formation, inflammation, cardiac fibrosis, hypertrophy, and dilatation; increased sudden cardiac death. | 913 |
| Doxorubicin | Mouse | Increased myocardial iNOS expression and nitrotyrosine formation, which correlates with cardiac dysfunction. | 883, 1355 |
| Doxorubicin | Mouse | Severe LV dysfunction and increased myocardial nitrotyrosine formation, matrix metalloproteinase activation in acute and chronic models of doxorubicin- induced heart failure, which are improved by peroxynitrite decomposition catalyst, FP-15. | 44, 985 |
| Chronic myocardial ischemia | Rat | Increased myocardial nitrotyrosine formation, decreased myofibrillar creatine kinase activity. | 878, 987 |
| Chronic myocardial ischemia | Mouse | Increased myocardial iNOS expression, plasma nitrate and nitrite concentrations, and myocardial and plasma nitrotyrosine levels in wild-type compared with iNOS(−/−) mice. Improved LV function in iNOS(−/−) compared with wild-type mice. | 383 |
| Pacing | Dog | Progressively increased cardiac dysfunction, nitrotyrosine formation, and cell death in myocytes. | 192 |
| HIV | Human | Increased myocardial nitrotyrosine formation in patients with HIV-induced dilated cardiomyopathy. | 201 |
| Idiopathic dilated cardiomyopathy | Human | Increased iNOS expression and/or activity in heart failure. | 389, 529, 1317, 1465 |
| Idiopathic dilated cardiomyopathy | Human | Increased iNOS protein expression that is associated with nitrotyrosine formation. Although iNOS-positive patients are generally characterized by larger LV volume and depressed function, the preserved NO generation appears to be associated with higher cardiac work due to the preserved Frank-Starling relationship in end-stage heart failure. | 1317 |
| Idiopathic dilated cardiomyopathy | Human | Increased nitration of SERCA2a in idiopathic dilated cardiomyopathic (DCM) hearts. Positive correlation between the time to half-relaxation and the nitrotyrosine/SERCA2a content in myocytes. | 789 |
| Atrial fibrillation | Human | Increased nitrotyrosine formation, which correlates with myofibrillar creatine kinase inhibition. | 881 |
| Atherosclerosis, restenosis, and hyperhomocysteinemia | |||
| Hypercholesterolemia, hyperlipidemia | Rabbit, mouse | The cholesterol-enriched diet increased vascular superoxide and NT formation, serum NT levels and induced endothelial dysfunction. Cicletanine, estradiol and fasting improved endothelial dysfunction, decreased the atherosclerosis progression and reduced serum or vascular NT level/staining. | 653, 1250, 1411 |
| Hypercholesterolemia | Human | Increased resting levels of ROS and peroxynitrite in leukocytes from patients with untreated hypercholesterolemia. | 343 |
| Atherosclerosis | Human | Increased 3-NT presence and iNOS expression in human atherosclerotic tissue that correlates with plaque instability in patients. | 49, 80, 164, 240, 313, 363, 584, 742, 802, 1019, 1211 |
| Vascular ballon injury (a model of restenosis) | Rat, rabbit | Increased 3-NT immunoreactivity, iNOS overexpression, and PARP activation in media and neointima following balloon injury. | 37, 82, 618, 667, 747, 921 |
| Vascular stent implantation | Human | Increased 3-NT/tyrosine ratio in the serum of patients following stent implantation that appeared to be an independent predictor of angiographic late lumen loss. | 602 |
| Hyperhomocysteinemia | Rat, mouse | Endothelial dysfunction, impaired flow-induced vasodilation, enhanced superoxide and peroxynitrite production and NAD(P)H oxidase expression in the vasculature, enhanced myocardial NT formation, and MMP activation. | 42, 70, 339, 579, 635, 912, 1181, 1303, 1431, 1435 |
| Aging | |||
| Aging | Rat | Cardiovascular dysfunction, increased superoxide and peroxynitrite formation, increased expression of NAD(P)H oxidases, iNOS, and PARP activation in aging vasculature and myocardium. Enhanced age-dependent nitration of various mitochondrial proteins (e.g., aconitase, creatine kinase, voltage-dependent anion channel, ATP synthase), sarcoplasmic reticular Ca2+-ATPases, and other proteins involved in blood coagulation, lipid transport, blood pressure regulation, and protease inhibition. | 7, 249, 409, 654, 676, 692, 991, 992, 1131, 1213, 1311, 1329, 1330, 1397 |
| Hypertension | |||
| Aortic banding | Mouse, rat | Increased superoxide formation, gene expression of several subunits of NAD(P)H oxidases, NOS, and NT in the aorta segment above aortic coarctation (hypertensive zone) and in hearts of aortic- banded rats and mice compared with normotensive controls. | 65, 125, 724, 1324 |
| SHR, M-SHRSP, SHR/NDmcr-cp (SHR/cp) | Rat | Increased peroxynitrite formation or protein nitration in the serum, vasculature, and kidneys of SHR, malignant stroke-prone spontaneously hypertensive (M-SHRSP) and SHR/NDmcr-cp (SHR/cp) rats (genetic model of the metabolic syndrome). Antioxidant rich diet, M40403 (superoxide dismutase mimetic), chlorogenic acid(polyphenol), ramipril (angiotensin-converting enzyme inhibitor), carvediiol (adrenoceptor blocker with antioxidant properties) and tetrahydrobiopterin (cofactor of eNOS) attenuated hypertension and NT formation in vasculature, kidneys, and improved compromised vascular function and end-organ damage. | 269, 565, 643, 776, 815, 1080, 1217, 1252, 1402 |
| Chronic ANG I infusion | Rat, mouse | Increased peroxynitrite formation and PARP activation in aorta, heart, and kidneys of rats and mice following chronic infusion and in endothelial cells in vitro. The protein nitration correlated with the extent of endothelial dysfunction observed and both were attenuated by supplementation with NOS cofactor tetrahydrobiopterin. | 492, 656, 880, 1159, 1236, 1342, 1349 |
| Obesity/diet | Rat | Long-term high-fat (primarily saturated) diet induced hypertension associated with increased accumulation of NT in aorta, heart, kidney, and liver. Conversion to low-fat diet normalized blood pressure and tissue NT content. | 327, 1077 |
| Lead | Rat | Lead-induced hypertension was associated with increased ROS- mediated inactivation of nitric oxide with sequential increase in 3- NT abundance in plasma, heart, kidney, and brain. Administration of high dose of vitamin E ameliorated hypertension and normalized tissue NT content without altering tissue lead content. | 325, 1323 |
| Renovascular clamping/renal failure | Rat | Increased NT formation in plasma, aorta, heart, and kidney of rats with renal hypertension [1KIC or 2KIC (one-kidney or two-kidney one-clip) and 5/6 nephrectomy]. This and hypertension were attenuated by angiotensin type I receptor inhibitor losartan, tempol, and high dose of vitamin E. | 119, 327, 1325 |
| Mineralocorticoid (aldosterone) | Rat | Chronic aldosterone/salt treatment induced time-dependent sustained activation of NADPH oxidase with 3-NT generation and nuclear factor κB activation in endothelial and inflammatory cells, which was attenuated by an aldosterone receptor antagonist spironolactone. | 1214 |
| Cyclosporin | Human | In kidney-transplanted patients with cyclosporin-induced hypertension, carvediol increased plasma antioxidant power and reduced 3-NT and TGF-β mRNA levels. | 170 |
| Hypertension, diabetes | Human cardiac myocytes | Increased apoptosis, necrosis, angiotensin II, and NT formation in myocytes. | 413 |
NT/3-NT, nitrotyrosine/3-nitrotyrosine; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase; LV, left ventricle/ventricular; PARP, poly(ADP-ribose) polymerase; HIV, human immunodeficiency virus; ANG II, angiotensin II; ROS, reactive oxygen species; SHR, spontaneous hypertensive rat.