The Role And Mechanism Of Transforming Growth Factor Beta 3 In Human Myocardial Infarction-induced Myocardial Fibrosis

BackgroundMyocardial remodeling after myocardial infarction(MI)is a major driving factor that accelerates heart failure.Several pathophysiological processes are involved in MI including cell apoptosis,hypertrophy,angiogenesis,synthesis and deposition of extracellular matrix.Excessive deposition of extracellular matrix will result in cardiac fibrosis,which leads to attenuate ventricular compliance,cardiac dysfunction and finally,heart failure.In the early phase of MI,cardiac fibroblasts(CFs),characterized by fundamental contribution to the cardiac response to various forms of injury,are collected to the infarcted area under the recruit of cytokines.In the maturation phase,the CFs secrete collagens and other extracellular matrix proteins to maintain the stability of the scar.Thus,regulating the synthesis and deposition of the collagen is the key step to improve the post-MI prognosis.The critical phase of these responses depend on the alteration of the cardiac microenvironment,which consists of inflammation change and proliferation of nonmyocytes.TGF?s,a multifunctional peptides superfamily,regulates cell growth and differentiation,and influences the action of the cellular receptors.Only the TGF?1,TGF?2,and TGF?3 isoforms have been isolated from human sources.A number of studies have shown this superfamily can affect a variety of biological behaviors of the collagen.In this regard,TGF?1 is a powerful initiator for the synthesis of collagen and other major extracellular matrix components in a variety of cell types.In contrast to the TGF?1,TGF?3 has shown the ability to down-regulate scarring and fibrosis in vivo under certain experimental conditions.TGF?3 expression was elevated predominantly in the infarcted area.This pronounced increase in TGF?3 persisted up to 82 days and correlated positively with the parameters of extracellular matrix metabolism.Thus,TGF?3 appeared to be a very promising candidate for the prognosis of the MI.However,the pathological roles of TGF?3 in post-MI fibrosis and molecular mechanisms underlying myocardial fibroblasts proliferation,migration and function remain poorly understood.Our previous study found that the increasing level of TGF?3 was proportional to the increasing level of Ang II.Lots of clinical data indicated that after MI,angiotensin converting enzyme inhibitor(ACEI)and the ATl receptor blocker(ARB)can significantly reduce the level and proportion of MI in myocardial remodeling,in which plays a positive role for improving the prognosis of patients,affirms the Ang II's important role in myocardial remodeling after myocardial infarction.Cardiac Ang II levels are quickly elevated after injury,and stimulation of CFs by Ang II induces proliferation and the expression of collagen.So we hypothesized that TGF?3 might have certain effects on Ang II-induced myocardial fibrosis.In this study,we checked the expression levels of TGF?3 in human myocardial infarction area,which were collected from the infracted area as compared with normal myocardial area.Subsequently,we applied Ang?-induced medium to the human CFs,and analyzed the effects of TGF?3 on cell proliferation,migration and the synthesis of collagen.To explore the possible molecular mechanism by which TGF?3 regulate the fibrotic potential,we analyzed the relative levels of TGF?/smad molecules and their phosphorylation.Finally,we examined the role of the smad7 in TGF?/smad signalling pathway.Results Our experiment revealed that TGF?3 up-regulation attenuated the proliferation and migration of human cardiac fibroblasts and the expression of Collagen? and Collagen ?,which are the main components of fibrosis.Meanwhile the expression of collagen? and collagen ? were higher in sismad7 group than the control group.Furthermore,it was observed that silencing smad7 promoted the phosphorylation level TGF? signaling.Collectively,these results indicated that TGF?3 inhibited the fibrosis via TGF?/smad signaling pathway,which may be attributed to the regulation of smad7.These findings suggested that TGF?3 may serve as a potential therapeutic target for myocardial fibrosis post-MI.Conclusion Our results suggested that TGF?3 could attenuate the proliferation,migration capability and collagen synthesis of human CFs by modulating the TGF?/smad signaling pathway,which might be attributed to the regulation of smad7.