Drug-targeted Inhibition Of Focal Adhesion Kinase On The Effects And Mechanisms Of Fibrosis After Myocardial Infarction

Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease.Research about adverse ventricular remodeling in post-myocardial infarction has been the focus of cardiovascular scientist.Cardiac fibrosis in post-myocardial infarction(MI),seen in both infarcted and non-infarcted myocardium,is beneficial to the recovery of heart function.But progressively pathological fibrosis impairs ventricular function and leads to poor prognosis.FAK has recently received attention as a potential mediator of fibrosis(Such as skin fibrosis,renal fibrosis,muscle fibrosis,pulmonary fibrosis and liver fibrosis,etc.).our previous study reported that pharmacological inhibition of FAK can attenuate cardiac fibrosis in post MI models.However,the long-term effects on cardiac function and adverse cardiac remodelling were not clearly investigated.In this study,we tried to determine the preliminary mechanisms in regulating CF transformation to myofibroblasts,migration and proliferation and ECM synthesis relevant to the development of adverse cardiac remolding in vitro.Our study provides even more evidence that FAK is directly related to the activation of CF in hypoxia condition in a dose-dependent and time-dependent manner.Pharmacological inhibition of FAK significantly reduces myofibroblast differentiation,decrease migratory and proliferation capability;Both PI3K/AKT signalling and ERK1/2 are necessary for hypoxia-induced CF differentiation and ECM synthesis;this process also involves lysyl oxidase(LOX).Our findings,for the first time,suggests that focal adhesion kinase regulates hypoxia-induced differentiation of cardiac fibroblasts,pharmacological inhibition of FAK may become an effective therapeutic strategy against adverse fibrosis.Under normal conditions,there is a balance between synthesis of extracellular matrix and degradation which is primarily mediated by matrix metalloproteinases and tissue inhibitors of metalloproteinases;but in the case of injury,this dynamic balance between the synthesis and degradation of the extracellular matrix is broken,leading to accumulation of collagen in the interstitial tissue.Excessive extracellular interstitial deposition increases ventricular stiffness,induce arrhythmias,leading to ventricular systolic diastolic dysfunction,and ultimately heart failure.The process of fibrosis after myocardial infarction can be roughly divided into two processes:reactive fibrosis and reparative fibrosis,reparative fibrosis occurs in the interstitium in response to myocyte apoptosis and necrosis which is most commonly present following myocardial ischemia and infarction,is important for maintaining the integrity of cardiac structural and function.Reactive fibrosis occurs in the infarcted and remote infarcted areas,and reactive fibrosis is often accompanied by local inflammation of the infarct region,which is characterized by extensive deposition of extracellular matrix in interstitial or perivascular.The fibrosis level of remote infarcted areas is closely related to the long-term prognosis after myocardial infarction.In the first part,We have confirmed that FAK involved in the regulation of fibroblast phenotype transformation and extracellular matrix synthesis under ischemia and hypoxia conditions in vitro.To further investigate the functional role of FAK in the process of post-MI interstitial fibrosis,the effect of a FAK inhibitor on post-MI fibrosis was evaluated using the MI model by constructing CD1 mice Arterial anterior descending artery ligation.After continuous administration of drugs at a given time point,the pathology and molecular biology was tested and cardiac function was evaluated.The results showed that,after the continuous administration of PF-573228,the FAK inhibitor significantly reduced excessive reactive interstitial fibrosis at the border and in remote areas.,this trend was more obvious especially in the infarcted and the non-infarcted area,peripheral vascular fibrosis has also been improved,indicating that targeted inhibition of FAK can offset the reactive fibrosis,reduce plasma BNP levels and improve the postoperative survival status of the mice.