Bone Morphogenetic Protein 6 Alleviates Cardiac Fibrosis and Dysfunction in Heart Failure

Abstract

Cardiac fibrosis, the main pathological process from ventricular remodeling to heart failure, has attracted much more attention in recent years. Transforming growth factor beta-1 (TGF-β1) plays a key role in the pathogenesis of cardiac fibrosis. Bone morphogenetic protein 6 (BMP6), a member of the TGF-β family, is reportedly involved in many fibrosis-related diseases, such as hepatic and renal fibrosis. Nevertheless, there are few reports about the specific role of BMP6 in cardiac fibrosis. Here, we demonstrated the protein levels of BMP6 were lower in patients with heart failure. In addition, BMP6 expression appeared lower in left ventricles of rats in a transverse aortic constriction (TAC) surgery group compared with the sham group. Next, we observed that silencing BMP6 using small interfering RNA remarkably aggravated TGF-β1-induced cardiac fibrosis, while overexpression of BMP6 by Adenovirus largely improved cardiac fibrosis. Moreover, we found that BMP6 played a protective role in cardiac fibrosis via inhibiting the TGF-β1/Smad3 pathway, that partially functioned via interferon regulatory factor 7 (IRF7) suppression. Finally, we introduced Adeno-associated virus-9 (AAV-9) carrying shBMP6 and found that TAC surgery-induced cardiac fibrosis was significantly aggravated, while administration of rh-BMP6 via tail vein injection markedly ameliorated cardiac fibrosis induced by knockdown of BMP6 in vivo. In conclusion, our study demonstrated that BMP6 may serve as a novel biomarker and a therapeutic target in heart failure related to cardiac fibrosis. \n \nFunding Statement: This study was supported by the National Natural Science Foundation of China [No. 81770242 to YaChen Zhang] and Natural Science Foundation of Ningbo (No:2019A610388). \n \nDeclaration of Interests: The authors declare that they have no conflicts of interest. \n \nEthics Approval Statement: The collection and use of human LV samples were approved by the local human research ethics committee of Shanghai Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine \n \nAnimal studies were approved by the Animal care and Use Committee of Shanghai Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine.