The Mechanism Of TGF-β1 Inducing Atrial Fibrosis And The Protective Effects Of MR Antagonist

Atrial fibrillation(AF)is the most common arrhythmia in the clinical practice.Atrial structural remodeling contributes to occurrence and maintenance of AF.Atrial fibrosis,a hallmark of atrial structural remodeling,largely determines the success of rhythm control in AF.The detailed mechanism underlying atrial fibrosis is still not fully clarified.Studies suggest that TGF-β1-induced atrial fibrosis may be a potential pathological factor of AF.The existing traditional antiarrhythmic drugs have shown unsatisfactory effects as well as obvious side effects.Thus,the upstream approach that targets pathologic processes involved in the atrial fibrosis has drawn much attention.Both the clinical studies and animal experiments suggest that MR antagonists play an important role in beneficially regulating AF and atrial fibrosis.However,the underlying mechanisms and the cellular target(s)of the MR antagonists in preventing atrial fibrosis have remained unclear.Therefore,we set out to study the effects of the MR antagonist on atrial fibrosis induced by TGF-β1 and investigate the underlying molecular mechanism in the Section one.Results of Section one show that EPL inhibited atrial fibrosis induced by TGF-β1 in vivo and in vitro.EPL blocked down-regulation of Smad7 and up-regulation of P-Smad2/3 induced by TGF-β1.This serves as a key mechanism through which EPL inhibited expression of fibrosis related molecules and atrial fibrosis.In addition,in vivo study suggests that smad7 may be a key therapeutic target for EPL in preventing atrial fibrosis.Then we explored the target cells of MR antagonists in Sections two and three.As the MR in macrophages are closely related to atrial fibrosis,for example,in human AF,macrophages are recruited to atria.In addition,MR deficiency in macrophages suppressed interstitial fibrosis in the ventricles.Therefore,in Section two,mice with genetic deletion of MR in macrophages were crossed with TGF-β1 transgenic mice to investigate the target cell of the MR.As a result,selective knockout of MR in macrophages did not significantly affect atrial fibrosis.As cardiac myocytes and fibroblasts are two major cell types in the atria and it is reported that MR deletion in cardiomyocytes can improve fibrosis after myocardial infarction.Therefore,in the Section three,Mice with genetic deletion of MR in cardiomyocytes were crossed with TGF-β1 transgenic mice.As a result,selective deletion of MR in cardiomyocytes did not significantly inhibit atrial fibrosis.In summary,our research showed that the emerging MR antagonist,EPL,inhibited the atrial fibrosis by suppressing the TGF-β1/smad signaling pathway,and Smad7 may be the key target.Macrophages and cardiomyocytes may not be the key target cells of EPL in preventing atrial fibrosis.