MARCH1 Deletion Attenuates HFpEF by Promoting Adipose Beiging.

Abstract

BACKGROUND: Membrane-associated RING-CH1 (MARCH1) is a critical membrane-bound RING domain E3 ubiquitin ligase that primarily regulates immune cell development, immune responses, antigen presentation modulation, and metabolic functions. Its role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF) remains elusive. This study aimed to investigate the function of MARCH1 in HFpEF. METHODS: Multi-hit (high fat/sugar diet together with deoxycorticosterone acetate and angiotensin II injection) HFpEF mouse model was established in C57BL/6 wild-type mice and MARCH1 KO mice. Non-HFpEF control mice received standard diet. Comprehensive evaluation was carried out through echocardiography, histological and biochemical studies. White adipose tissue (WAT) beiging was analyzed in isolated stromal vascular fraction cells. The relevant molecular mechanisms were determined through RNA sequencing and co-immunoprecipitation assay. RESULTS: Cardiometabolic dysregulation with hypertension and obesity was observed in WT HFpEF mice. Significantly reduced running distance and running time were found in HFpEF mice compared to the WT control mice (both p&#x2009;<&#x2009;0.05). Histologic and echocardiographic examinations also visualized cardiac fibrosis, left ventricular hypertrophy, and diastolic dysfunction in HFpEF mice. MARCH1 expression was significantly upregulated in the WAT of HFpEF mice. MARCH1 deficiency alleviated cardiac dysfunction of HFpEF mice and induced WAT beiging following HFpEF. Mechanistically, MARCH1 contributes to HFpEF by direct binding to Kr&#xfc;ppel-like factor 15 (KLF15). Overexpressing KLF15 blocked the beiging effects of WAT from MARCH1 KO mice. CONCLUSION: Our study highlights the positive anti-fibrotic and WAT beiging effects of MARCH1 inhibition in the setting of HFpEF. Targeting MARCH1 and KLF15 might serve as novel therapeutic options for HFpEF.