Phospholipid remodeling of the cardiomyocyte membrane affects cardiac function

Membrane phospholipid (PL) remodeling has been linked to various mammalian metabolic and oncogenic pathologies, but its role in the heart remains elusive. Here, we investigated the role of PL remodeling in cardiac function. Lysophospholipid acyltransferase 7 (LPLAT7)/lysophosphatidylglycerol acyltransferase 1 (LPGAT1) remodels phosphatidylcholine (PC) and phosphatidylethanolamine (PE), two major cardiac membrane PL species. Public functional genomics data revealed downregulation of LPLAT7/LPGAT1 gene expression in failing human hearts and murine cardiomyocytes. Cardiomyocyte-specific Lplat7/Lpgat1-deficient male mice exhibited selective remodeling of cardiac PC and PE composition, including diminished stearic acid- and docosahexaenoic acid (DHA)-enriched species. LPLAT7/LPGAT1 suppression induced myocardial contractile dysfunction associated with cAMP-dependent protein kinase (PKA) activation and abnormal calcium handling, partially rescued by pharmacological PKA inhibition. Conversely, Lplat7/Lpgat1 overexpression partially improved pressure overload-induced cardiac dysfunction with selective restoration of PC(40:6), a major stearic acid/DHA-enriched PC species. These findings highlight the contributory role of LPLAT7/LPGAT1-dependent membrane PL remodeling in cardiac function and heart failure. Cardiomyocyte LPLAT7/LPGAT1 regulates membrane phospholipid composition and cardiac function. Its loss reduces stearic acid- and DHA-enriched phosphatidylcholine and causes PKA activation, abnormal calcium handling, and contractile dysfunction, whereas overexpression partially improves pressure overload-induced dysfunction