Deletion of Microfibrillar-Associated Protein 4 Attenuates Left Ventricular Remodeling and Dysfunction in Heart Failure

Abstract

Background: Cardiac remodeling predisposes the heart to failure (HF) if the burden not solved, and HF is a growing cause of morbidity and mortality worldwide. Cardiac extracellular matrix (ECM) not only by providing structural support, but also a core aspect of myocardial response to various biomechanical stress and HF. Microfibrillar-associated protein 4 (MFAP4) is an integrin ligand and located in the ECM, whose biological functions in heart remain poorly understood. In the current study we aimed to test the role of MFAP4 in cardiac remodeling. Methods: MFAP4-deficient (MFAP4-/-) and wild type (WT) mice were subjected to aortic banding (AB) surgery and isoproterenol (ISO) induced models of cardiac remodeling. And evaluate the functional effect of MFAP4 on cardiac hypertrophy, fibrosis, cardiac electrical remodeling. Findings: The expression level of MFAP4 was increased in animal cardiac remodeling models induced by pressure load and ISO. When challenged with 8 weeks AB or 2 weeks ISO intraperitoneal, MFAP4 -/- mice exhibited lower levels of cardiac fibrosis and fewer ventricular arrhythmias. However, it has no significant effect on cardiomyocyte hypertrophy. Interpretation: These findings are the first to demonstrate an inhibitory role of MFAP4 deficiency on cardiac fibrosis and ventricular arrhythmias, but has no significant effect on hypertrophy response. Funding Statement: This work was supported by grants from the Key Project of the National Natural Science Foundation (No. 81530012); National Key RD Development Center for Medical Science and Technology National Health and Family Planning Commission of the People's Republic of China (The prevention and control project of cardiovascular disease, 2016ZX-008-01); the Fundamental Research Funds for the Central Universities (2042018kf1032). Declaration of Interests: The authors have declared no conflicts of interest. Ethics Approval Statement: All animal studies adhered to the guidelines for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (NIH Publication, revised 2011) and the guidelines of the Animal Care and Use Committee of Renmin Hospital of Wuhan University.