Skip to main content
NCBI home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2005 Mar;64(3):382–387. doi: 10.1136/ard.2004.023382

Increased circulating levels of tissue kallikrein in systemic sclerosis correlate with microvascular involvement

A Del Rosso 1, O Distler 1, A Milia 1, C Emanueli 1, L Ibba-Manneschi 1, S Guiducci 1, M Conforti 1, S Generini 1, A Pignone 1, S Gay 1, P Madeddu 1, M Matucci-Cerinic 1
PMCID: PMC1755411  PMID: 15708892

Abstract

Background: In systemic sclerosis (SSc) the lack of an angiogenic response to hypoxia may be due to inappropriate synthesis of angiogenic and angiostatic factors. Tissue kallikrein (t-kallikrein), regulating the kallikrein-kinin system and acting on the microcirculation, is a potent angiogenic agent, and kallistatin is its natural inhibitor.

Objective: To evaluate, in patients with SSc, t-kallikrein and kallistatin levels and their correlation with clinical features and measures of microvascular involvement.

Patients and methods: Serum levels of t-kallikrein and kallistatin (ELISA) and t-kallikrein skin expression (immunohistochemistry) were studied in patients with SSc, and evaluated for subset (dSSc or lSSc), clinical and immunological features, and microvascular involvement (ulcers, telangiectasias, nailfold videocapillaroscopy).

Results: Circulating levels of t-kallikrein were higher in SSc than in controls (p<0.001). T-kallikrein did not differ between lSSc and dSSc, although it was higher in lSSc than in controls (p<0.001).T-kallikrein levels were higher in patients with early and active capillaroscopic pattern than in those with late pattern (p = 0.019 and 0.023). Patients with giant capillaries and capillary microhaemorrhages had higher t-kallikrein concentrations than patients with architectural derangement (p = 0.04). No differences in kallistatin levels were detected between patients with SSc and controls, or between lSSc and dSSc. In early SSc skin, the presence of t-kallikrein was found in endothelial and in perivascular inflammatory cells, while no staining in skin of advanced SSc was detected.

Conclusion: T-kallikrein levels are increased in patients with SSc, particularly in lSSc, and are associated with early and active capillaroscopic patterns. T-kallikrein may play a part in SSc microvascular changes.

Full Text

The Full Text of this article is available as a PDF (164.3 KB).

Figure 1.

Figure 1

Open in a new tab

 The kallikrein-kinin system (KKS) and its putative actions in SSc. T-kallikrein cleaves kinins (bradykinin and lysil-bradykinin) from low molecular weight kininogen (LMWK) and high molecular weight kininogen (HMWK). Kinins released from the vascular endothelium interact with B1 receptors (constitutively expressed) and B2 receptors (induced by tissue damage and inflammation) of endothelial and vascular smooth muscle cells. Kinins are rapidly inactivated mainly by angiotensin converting enzyme (ACE, kininase II). EC, endothelial cells.

Figure 2.

Figure 2

Open in a new tab

 T-kallikrein levels in SSc, lSSc, dSSc, and controls. *Significantly higher versus controls.

Figure 3.

Figure 3

Open in a new tab

 (A) T-kallikrein levels in SSc according to capillaroscopic pattern (early versus active versus late); *significantly higher in early and active versus controls. (B) T-kallikrein levels according to single capillaroscopic changes (patients with giants capillaries and microhaemorrhages versus patients with architectural derangement of capillaries); *significantly higher in the group with haemorrhages and giant capillaries than in the group with architectural derangement.

Figure 4.

Figure 4

Open in a new tab

 Skin sections. Immunostaining for t-kallikrein with diaminobenzidine revelation and Mayer's haematoxylin counterstaining. (A) Control: vessels with positive endothelial cells (arrows); (B) early SSc: small vessels show t-kallikrein staining in endothelial cells and in perivascular inflammatory infiltrate (arrow); (C) advanced SSc: no immunostaining for t-kallikrein is detected in the vessel wall.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahluwalia A., Perretti M. B1 receptors as a new inflammatory target. Could this B the 1? Trends Pharmacol Sci. 1999 Mar;20(3):100–104. doi: 10.1016/s0165-6147(99)01321-8. [DOI] [PubMed] [Google Scholar]
  2. Bhoola K. D., Figueroa C. D., Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev. 1992 Mar;44(1):1–80. [PubMed] [Google Scholar]
  3. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000 Apr;6(4):389–395. doi: 10.1038/74651. [DOI] [PubMed] [Google Scholar]
  4. Cerinic M. M., Generini S., Pignone A. New approaches to Raynaud's phenomenon [corrected]. Curr Opin Rheumatol. 1997 Nov;9(6):544–556. doi: 10.1097/00002281-199711000-00011. [DOI] [PubMed] [Google Scholar]
  5. Chao J., Miao R. Q., Chen V., Chen L. M., Chao L. Novel roles of kallistatin, a specific tissue kallikrein inhibitor, in vascular remodeling. Biol Chem. 2001 Jan;382(1):15–21. doi: 10.1515/BC.2001.003. [DOI] [PubMed] [Google Scholar]
  6. Chao J., Schmaier A., Chen L. M., Yang Z., Chao L. Kallistatin, a novel human tissue kallikrein inhibitor: levels in body fluids, blood cells, and tissues in health and disease. J Lab Clin Med. 1996 Jun;127(6):612–620. doi: 10.1016/s0022-2143(96)90152-3. [DOI] [PubMed] [Google Scholar]
  7. Clements P., Lachenbruch P., Siebold J., White B., Weiner S., Martin R., Weinstein A., Weisman M., Mayes M., Collier D. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol. 1995 Jul;22(7):1281–1285. [PubMed] [Google Scholar]
  8. Cutolo M., Sulli A., Pizzorni C., Accardo S. Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J Rheumatol. 2000 Jan;27(1):155–160. [PubMed] [Google Scholar]
  9. Cutolo Maurizio, Grassi Walter, Matucci Cerinic Marco. Raynaud's phenomenon and the role of capillaroscopy. Arthritis Rheum. 2003 Nov;48(11):3023–3030. doi: 10.1002/art.11310. [DOI] [PubMed] [Google Scholar]
  10. Desrivières S., Lu H., Peyri N., Soria C., Legrand Y., Ménashi S. Activation of the 92 kDa type IV collagenase by tissue kallikrein. J Cell Physiol. 1993 Dec;157(3):587–593. doi: 10.1002/jcp.1041570319. [DOI] [PubMed] [Google Scholar]
  11. Distler Oliver, Distler Jörg H. W., Scheid Annette, Acker Till, Hirth Astrid, Rethage Janine, Michel Beat A., Gay Renate E., Müller-Ladner Ulf, Matucci-Cerinic Marco. Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res. 2004 Jun 3;95(1):109–116. doi: 10.1161/01.RES.0000134644.89917.96. [DOI] [PubMed] [Google Scholar]
  12. Douillet C. D., Velarde V., Christopher J. T., Mayfield R. K., Trojanowska M. E., Jaffa A. A. Mechanisms by which bradykinin promotes fibrosis in vascular smooth muscle cells: role of TGF-beta and MAPK. Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H2829–H2837. doi: 10.1152/ajpheart.2000.279.6.H2829. [DOI] [PubMed] [Google Scholar]
  13. Emanueli C., Madeddu P. Targeting kinin receptors for the treatment of tissue ischaemia. Trends Pharmacol Sci. 2001 Sep;22(9):478–484. doi: 10.1016/s0165-6147(00)01761-2. [DOI] [PubMed] [Google Scholar]
  14. Emanueli C., Minasi A., Zacheo A., Chao J., Chao L., Salis M. B., Straino S., Tozzi M. G., Smith R., Gaspa L. Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Circulation. 2001 Jan 2;103(1):125–132. doi: 10.1161/01.cir.103.1.125. [DOI] [PubMed] [Google Scholar]
  15. Emanueli C., Zacheo A., Minasi A., Chao J., Chao L., Salis M. B., Stacca T., Straino S., Capogrossi M. C., Madeddu P. Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle. Arterioscler Thromb Vasc Biol. 2000 Nov;20(11):2379–2385. doi: 10.1161/01.atv.20.11.2379. [DOI] [PubMed] [Google Scholar]
  16. Hall J. M. Bradykinin receptors: pharmacological properties and biological roles. Pharmacol Ther. 1992 Nov;56(2):131–190. doi: 10.1016/0163-7258(92)90016-s. [DOI] [PubMed] [Google Scholar]
  17. Hayashi R., Yamashita N., Matsui S., Maruyama M., Sugiyama E., Sugiyama S., Kobayashi M. Bradykinin stimulates interleukin-8 production by human lung fibroblasts. Immunology. 1998 Dec;95(4):507–511. doi: 10.1046/j.1365-2567.1998.00649.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hebbar M., Peyrat J. P., Hornez L., Hatron P. Y., Hachulla E., Devulder B. Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis. Arthritis Rheum. 2000 Apr;43(4):889–893. doi: 10.1002/1529-0131(200004)43:4<889::AID-ANR21>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]
  19. Knox A. J., Corbett L., Stocks J., Holland E., Zhu Y. M., Pang L. Human airway smooth muscle cells secrete vascular endothelial growth factor: up-regulation by bradykinin via a protein kinase C and prostanoid-dependent mechanism. FASEB J. 2001 Nov;15(13):2480–2488. doi: 10.1096/fj.01-0256com. [DOI] [PubMed] [Google Scholar]
  20. Koch A. E., Litvak M. A., Burrows J. C., Polverini P. J. Decreased monocyte-mediated angiogenesis in scleroderma. Clin Immunol Immunopathol. 1992 Aug;64(2):153–160. doi: 10.1016/0090-1229(92)90193-r. [DOI] [PubMed] [Google Scholar]
  21. Koch A. E. The role of angiogenesis in rheumatoid arthritis: recent developments. Ann Rheum Dis. 2000 Nov;59 (Suppl 1):i65–i71. doi: 10.1136/ard.59.suppl_1.i65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. LeRoy E. C., Black C., Fleischmajer R., Jablonska S., Krieg T., Medsger T. A., Jr, Rowell N., Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb;15(2):202–205. [PubMed] [Google Scholar]
  23. Linz W., Wiemer G., Gohlke P., Unger T., Schölkens B. A. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev. 1995 Mar;47(1):25–49. [PubMed] [Google Scholar]
  24. Madeddu P., Gherli T., Bacciu P. P., Maioli M., Glorioso N. A kallikrein-like enzyme in human vascular tissue. Am J Hypertens. 1993 May;6(5 Pt 1):344–348. doi: 10.1093/ajh/6.5.344. [DOI] [PubMed] [Google Scholar]
  25. Mahabeer R., Bhoola K. D. Kallikrein and kinin receptor genes. Pharmacol Ther. 2000 Oct;88(1):77–89. doi: 10.1016/s0163-7258(00)00080-2. [DOI] [PubMed] [Google Scholar]
  26. Majewski S., Skopinska-Rozewska E., Jablonska S., Polakowski I., Pawinska M., Marczak M., Szmurlo A. Modulatory effect of sera from scleroderma patients on lymphocyte-induced angiogenesis. Arthritis Rheum. 1985 Oct;28(10):1133–1139. doi: 10.1002/art.1780281009. [DOI] [PubMed] [Google Scholar]
  27. Maricq H. R., Harper F. E., Khan M. M., Tan E. M., LeRoy E. C. Microvascular abnormalities as possible predictors of disease subsets in Raynaud phenomenon and early connective tissue disease. Clin Exp Rheumatol. 1983 Jul-Sep;1(3):195–205. [PubMed] [Google Scholar]
  28. Matucci-Cerinic M., Jaffa A., Kahaleh B. Angiotensin converting enzyme: an in vivo and in vitro marker of endothelial injury. J Lab Clin Med. 1992 Sep;120(3):428–433. [PubMed] [Google Scholar]
  29. Miao Robert Q., Agata Jun, Chao Lee, Chao Julie. Kallistatin is a new inhibitor of angiogenesis and tumor growth. Blood. 2002 Nov 1;100(9):3245–3252. doi: 10.1182/blood-2002-01-0185. [DOI] [PubMed] [Google Scholar]
  30. Morbidelli L., Parenti A., Giovannelli L., Granger H. J., Ledda F., Ziche M. B1 receptor involvement in the effect of bradykinin on venular endothelial cell proliferation and potentiation of FGF-2 effects. Br J Pharmacol. 1998 Jul;124(6):1286–1292. doi: 10.1038/sj.bjp.0701943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Murohara T., Asahara T., Silver M., Bauters C., Masuda H., Kalka C., Kearney M., Chen D., Symes J. F., Fishman M. C. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest. 1998 Jun 1;101(11):2567–2578. doi: 10.1172/JCI1560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Naidoo Y., Snyman C., Raidoo D. M., Bhoola K. D., Kemme M., Müller-Esterl W. Cellular visualization of tissue prokallikrein in human neutrophils and myelocytes. Br J Haematol. 1999 Jun;105(3):599–612. doi: 10.1046/j.1365-2141.1999.01391.x. [DOI] [PubMed] [Google Scholar]
  33. Pieri L., Sassoli C., Romagnoli P., Domenici L. Use of periodate-lysine-paraformaldehyde for the fixation of multiple antigens in human skin biopsies. Eur J Histochem. 2002;46(4):365–375. doi: 10.4081/1749. [DOI] [PubMed] [Google Scholar]
  34. Plendl J., Snyman C., Naidoo S., Sawant S., Mahabeer R., Bhoola K. D. Expression of tissue kallikrein and kinin receptors in angiogenic microvascular endothelial cells. Biol Chem. 2000 Nov;381(11):1103–1115. doi: 10.1515/BC.2000.135. [DOI] [PubMed] [Google Scholar]
  35. Porcu Paolo, Emanueli Costanza, Kapatsoris Maria, Chao Julie, Chao Lee, Madeddu Paolo. Reversal of angiogenic growth factor upregulation by revascularization of lower limb ischemia. Circulation. 2002 Jan 1;105(1):67–72. doi: 10.1161/hc0102.101360. [DOI] [PubMed] [Google Scholar]
  36. Ricupero D. A., Romero J. R., Rishikof D. C., Goldstein R. H. Des-Arg(10)-kallidin engagement of the B1 receptor stimulates type I collagen synthesis via stabilization of connective tissue growth factor mRNA. J Biol Chem. 2000 Apr 28;275(17):12475–12480. doi: 10.1074/jbc.275.17.12475. [DOI] [PubMed] [Google Scholar]
  37. Sardi S. P., Ares V. R., Errasti A. E., Rothlin R. P. Bradykinin B1 receptors in human umbilical vein: pharmacological evidence of up-regulation, and induction by interleukin-1 beta. Eur J Pharmacol. 1998 Oct 9;358(3):221–227. doi: 10.1016/s0014-2999(98)00609-8. [DOI] [PubMed] [Google Scholar]
  38. Tiffany C. W., Burch R. M. Bradykinin stimulates tumor necrosis factor and interleukin-1 release from macrophages. FEBS Lett. 1989 Apr 24;247(2):189–192. doi: 10.1016/0014-5793(89)81331-6. [DOI] [PubMed] [Google Scholar]
  39. Wolf W. C., Harley R. A., Sluce D., Chao L., Chao J. Localization and expression of tissue kallikrein and kallistatin in human blood vessels. J Histochem Cytochem. 1999 Feb;47(2):221–228. doi: 10.1177/002215549904700210. [DOI] [PubMed] [Google Scholar]
  40. Wu H. F., Venezie R. D., Cohen W. M., Jenzano J. W., Featherstone G. L., Lundblad R. L. Identification of tissue kallikrein messenger RNA in human neutrophils. Agents Actions. 1993 Jan;38(1-2):27–31. doi: 10.1007/BF02027209. [DOI] [PubMed] [Google Scholar]
  41. Xiong W., Tang C. Q., Zhou G. X., Chao L., Chao J. In vivo catabolism of human kallikrein-binding protein and its complex with tissue kallikrein. J Lab Clin Med. 1992 May;119(5):514–521. [PubMed] [Google Scholar]
  42. Yousef G. M., Diamandis E. P. The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev. 2001 Apr;22(2):184–204. doi: 10.1210/edrv.22.2.0424. [DOI] [PubMed] [Google Scholar]
  43. Zhou G. X., Chao L., Chao J. Kallistatin: a novel human tissue kallikrein inhibitor. Purification, characterization, and reactive center sequence. J Biol Chem. 1992 Dec 25;267(36):25873–25880. [PubMed] [Google Scholar]
  44. Ziche M., Morbidelli L., Masini E., Amerini S., Granger H. J., Maggi C. A., Geppetti P., Ledda F. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest. 1994 Nov;94(5):2036–2044. doi: 10.1172/JCI117557. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Publishing Group

RESOURCES