Apolipoprotein M: A liver-derived lipid-binding protein protects against heart failure with preserved ejection fraction by inhibiting TGF-β signaling.

BACKGROUND: Visceral and hepatic adiposity and associated inflammation are recognized as prominent features of heart failure (HF) with preserved ejection fraction (HFpEF). Apolipoprotein M (ApoM), a liver-derived lipid-binding protein, exerts anti-inflammatory and cardioprotective effects, and its expression decreases during obesity. However, its role in HFpEF remains unclear. METHODS: Plasma proteomic data from the UK Biobank were analyzed using integrated bioinformatics and machine-learning approaches. A mouse model of HFpEF was established using a high-fat diet combined with Nω-nitro-L-arginine methyl ester (L-NAME). The role of ApoM was investigated using recombinant adeno-associated virus serotype 8-mediated overexpression and knockdown, as well as global ApoM-knockout mice. The underlying molecular mechanisms were examined using RNA sequencing and co-immunoprecipitation (CO-IP). RESULTS: Plasma proteomic profiling identified ApoM as an HF-associated protein. Lower plasma ApoM abundance was independently associated with incident HF but was not correlated with left ventricular ejection fraction (LVEF). In the mouse model of HFpEF, circulating ApoM levels were inversely associated with the severity of diastolic dysfunction. ApoM deficiency aggravated diastolic dysfunction and adverse myocardial remodeling, whereas liver-specific ApoM overexpression attenuated these changes. Mechanistically, ApoM inhibited transforming growth factor-β (TGF-β)/SMAD2/3-mediated profibrotic signaling in the cardiac through interactions with TGF-β receptor type 1 (TGFBR1) and TGFBR2. Pharmacological inhibition of TGFBR1 with SB505124 ameliorated the HFpEF phenotype in ApoM-knockout mice. CONCLUSIONS: ApoM, a novel mediator of liver-heart crosstalk, protects against HFpEF by inhibiting TGF-β signaling. ApoM may serve as a potential therapeutic target in HFpEF.