Deletion of the E3 ubiquitin ligase MARCH1 promotes white adipose tissue beiging and attenuates diastolic dysfunction in a multi-hit mouse model of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) represents a pervasive health challenge with substantial morbidity and mortality rates. The intricate underlying molecular mechanisms of HFpEF remain elusive. Aberrant regulation of ubiquitination is likely associated with several diseases, including various types of metabolic diseases. E3 ubiquitin ligases are regarded as the most influential ubiquitin enzymes. The objective of this study was to investigate the potential role of the E3 ubiquitin ligase membrane-associated RING-CH-1 (MARCH1) in the pathogenesis of HFpEF and related therapeutic implication of modulating MARCH1 in HFpEF.

In this study, a multi-hit mouse model, induced by a combination of high-fat diet (HFD), DOCA, and ANGII, successfully replicates the extensive systemic and cardiovascular characteristics observed in human HFpEF. Body weight was 27.58±0.45 and 30.60±1.48 in sham and HFpEF group respectively (p=0.0031). Systolic blood pressure (SBP) was 129.8±8.73 and 150.7±8.74 mmHg in sham and HFpEF group respectively (p=0.0013). Diastolic blood pressure (DBP) was 101.8±5.22 and 110.8±8.66 in sham and HFpEF group respectively (p=0.049). The E/A ratio was 1.51±0.22 and 0.98±0.04 in sham and HFpEF group respectively (p=0.0002). The E/e’ ratio was 22.46±2.22 and 37.00±5.27 in sham and HFpEF group respectively (p<0.0001). Significant upregulation of MARCH1 expression was observed in both cardiac tissue and white adipose tissue derived from HFpEF mice. Diastolic dysfunction was significantly attenuated in the multi-hit stimulated MARCH1 knock-out mice as compared to WT mice. E/A was 1.59±0.21, 1.1±0.07, 1.72±0.74, and 1.54±0.28 in WT-sham, WT-HFpEF, M1-/--sham and M1-/--HFpEF groups respectively (P<0.0001). E/e’ was 22.02±2.44, 34.08±5.95, 22.60±2.23 and 25.86±2.41 in WT-sham, WT-HFpEF, M1-/--sham and M1-/--HFpEF groups respectively (P<0.0001). Deletion of MARCH1 also led to enhanced white adipose tissue beiging.

Our findings indicate the potential therapeutic role of March1 inhibition in improving cardiac diastolic function and enhancing white adipose tissue beiging in the setting of HFpEF.