The autocrine role of tryptase in pressure overload-induced mast cell activation, chymase release and cardiac fibrosis

Abstract

Background Cardiac mast cell (MC) proteases, chymase and tryptase, increase proliferation and collagen synthesis in cultured cardiac fibroblasts. However, the question as to why preventing individually the actions of either protease prevents fibrosis when both are released upon MC activation remains unanswered. Since tryptase has the ability to activate MCs in noncardiac tissues via the protease-activated receptor-2 (PAR-2), there is the possibility that its, in vivo, fibrotic role is due to its ability to induce MC degranulation thereby amplifying the release of chymase. Methods This study sought to delineate the interactions between tryptase and chymase in myocardial remodeling secondary to transverse aortic constriction (TAC) for 5 wks in male Sprague Dawley rats untreated or treated with either the tryptase inhibitor, nafamostat mesilate or MC membrane stabilizing drug, nedocromil (n=6/group). In addition, ventricular slices from 6 rat hearts were incubated with tryptase, tryptase plus nafamostat mesilate or chymostatin for 24 h. Results and Conclusion The results indicate the presence of PAR-2 on MCs and that tryptase inhibition and nedocromil prevented TAC-induced fibrosis and increases in MC density, activation, and chymase release. Tryptase also significantly increased chymase concentration in ventricular tissue culture media, which was prevented by the tryptase inhibitor. Hydroxyproline concentration in culture media was significantly increased with tryptase incubation as compared to the control group and the tryptase group incubated with nafamostat mesilate or chymostatin. We conclude that tryptase contributes to TAC-induced cardiac fibrosis primarily via activation of MCs and the amplified release of chymase.

The controversial role of mast cells in fibrosis

“…As a pharmacological approach to address the role of tryptase in fibrotic conditions in vivo, Li et al induced cardiac fibrosis in rats by transverse aortic constriction and treated the animals with a selective tryptase inhibitor (nafamostat mesylate). It was found that tryptase inhibition led to ameliorated cardiac fibrosis, in line with a pro‐fibrotic impact of MC tryptase.…”

“…In a model of 2,4,6,‐trinitrobenzene sulfonic acid‐induced colitis, Xu et al demonstrated that nedocromil, a cromoglycate derivative, reduced the extent of fibrosis. Nedocromil has also been demonstrated to ameliorate left ventricular fibrosis in spontaneously hypertensive rats and to reduce cardiac fibrosis resulting from transverse aortic constriction . Another MC “stabiliser”, Tranilast, reduced the extent of experimentally induced fibrosis in mice .…”

“…231 In addition, chymase inhibition using various compounds has been demonstrated to reduce cardiac fibrosis and Ang II production in diabetic hamsters, 232 cardiac fibrosis after ischemia reperfusion injury, 233 silica-induced pulmonary fibrosis in mice, 234 CCl 4 -induced liver fibrosis in hamsters, 235 tubulointerstitial fibrosis in obstructed kidneys in hamsters, 236 cardiac fibrosis in rats subjected to ligation of the left anterior descending coronary artery, 237 cardiac fibrosis in cardiomyopathic hamsters 238 and cardiac fibrosis in dogs subjected to tachycardia-induced heart failure. 239 As a pharmacological approach to address the role of tryptase in fibrotic conditions in vivo, Li et al 240 induced cardiac fibrosis in rats by transverse aortic constriction and treated the animals with a selective tryptase inhibitor (nafamostat mesylate). It was found that tryptase inhibition led to ameliorated cardiac fibrosis, in line with a pro-fibrotic impact of MC tryptase.…”

“…The traditional approach commonly perceived to prevent MC activation in disease has been the use of drugs labelled as "MC 243 and to reduce cardiac fibrosis resulting from transverse aortic constriction. 240 Another MC "stabiliser", Tranilast, reduced the extent of experimentally induced fibrosis in mice. 180 However, Tranilast was equally efficient in MC-competent vs -deficient mice, 180 suggesting that the impact of Tranilast was not due to effects mediated by MCs.…”

Intracrine angiotensin II functions originate from noncanonical pathways in the human heart

“…Mechanisms associated with chymase-mediated cardiac Ang II production may be influenced by multiple factors other than stretch since chronic estrogen treatment attenuates the increases in cardiac Ang II, Ang-(1-7), chymase mRNA, and mast cell number induced in oophorectomized mRen2.Lewis hypertensive rats (150,159). In addition, Li et al (83) reported recently that chymase and tryptase induction of cardiac fibrosis may require the proteaseactivated receptor-2 (PAR-2).…”