Lipin1 protects against ischemic heart damage by regulating myocardial lipid metabolism

Abstract Background Heart failure, a major contributor to morbidity and mortality worldwide, has been associated with disruptions in cardiac lipid metabolism, which also plays a critical role in vascular health. Lipin1, a multifunctional protein, acts as a phosphatidate phosphatase to generate diacylglycerol from phosphatidic acid and serves as a transcriptional cofactor to regulate lipid metabolism genes. Despite its known roles, the specific impact of lipin1 on cardiac remodeling after myocardial infarction (MI) remains unclear. Purpose This study aimed to investigate the role of lipin1 in cardiac remodeling after MI and to assess its potential as a protective factor in ischemic myocardium through lipid metabolism regulation. Methods We assessed lipin1 expression in cardiomyocytes of human failing hearts and murine myocardial infarction models. To examine its functional role, we used cardiomyocyte-specific Lpin1 knockout (cKO) and cardiomyocyte-specific Lpin1 overexpression (cOE) mice. Following MI induction, cardiac morphology and function were evaluated via echocardiography, while fibrosis, reactive oxygen species (ROS) levels, and inflammatory cytokines were assessed through histological and molecular analyses. Cardiac lipid droplet (LD), triglyceride, and free fatty acid content were also measured, along with the expression of fatty acid oxidation genes, such as Ppargc1a (PGC1α) and Acaa2. Results Lipin1 expression significantly decreased in cardiomyocytes from both human failing hearts and murine ischemic myocardium. cKO mice showed adverse remodeling post-MI, characterized by left ventricular dilation, reduced fractional shortening, increased fibrosis, elevated ROS, and heightened inflammatory cytokine expression, compared to controls. Conversely, cOE mice demonstrated improved cardiac function, with reduced fibrosis and inflammation relative to controls. MI induced a reduction in cardiac LDs in wild-type (WT) mice, further diminished in cKO hearts, along with decreased triglyceride and free fatty acid levels. In contrast, cOE hearts maintained higher LD levels and lipid content. Expression of fatty acid oxidation genes was downregulated in MI hearts of cKO mice but upregulated in cOE mice. Conclusion(s) Lipin1 plays a protective role in ischemic cardiomyocytes by preserving lipid metabolism, thereby mitigating myocardial remodeling and improving cardiac function post-MI. These findings suggest that lipin1 regulation of cardiac lipid homeostasis may offer a therapeutic target for preventing heart failure progression following ischemic injury.