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Myocardial infarction and reperfusion constitute a complex injury consisting of many distinct molecular stress patterns that influence cardiomyocyte survival and adaptation. Cell signalling, which is essential to cardiac development, also presents potential disease-modifying opportunities to recover and limit myocardial injury or maladaptive remodelling. Here, we hypothesized that Yap signalling could be sensitive to one or more molecular stress patterns associated with early acute ischemia. We found that Yap, and not Taz, expression patterns differed in a post-myocardial infarct compared to a peri-infarct region of rat hearts post-myocardial infarction, suggesting cell specificity that would be challenging to resolve for causation in vivo. Using H9c2 ventricular myotubes in vitro as a model, Yap levels were determined to be more sensitive to nutrient deprivation than other stress patterns typified by ischemia within the first hour of stress. Moreover, this is mediated by amino acid availability, predominantly L-isoleucine, and influences the expression of connective tissue growth factor (Ctgf)—a major determinant of myocardial adaptation after injury. These findings present novel opportunities for future therapeutic development and risk assessment for myocardial injury and adaptation. [ABSTRACT FROM AUTHOR]

Lipid phosphate phosphatase 3 (LPP3) is a membrane-bound enzyme that hydrolyzes lipid phosphates including the bioactive lipid, lysophosphatidic acid (LPA). Elevated circulating LPA production and cellular LPA signaling are implicated in obesity-induced metabolic and cardiac dysfunction. Deletion of LPP3 in the cardiomyocyte increases circulating LPA levels and causes heart failure and mitochondrial dysfunction in mice. To examine the influence of LPP3 modulation in the cardiomyocyte on obesity-induced cardiomyopathy, we generated mice with cardiomyocyte-specific LPP3 overexpression (LPP3 OE mice) driven by the α myosin heavy chain promoter. Female and male control (LPP3 FL ) and LPP3 OE mice were fed low-fat diet (LFD) or high-fat diet (HFD) for up to 22-23 wk, followed by the analysis of glucose homeostasis, cardiac function, plasma LPA levels, and mitochondrial respiration in cardiac myofibers. On LFD, both female and male LPP3 OE mice had markedly reduced plasma LPA levels and increased pyruvate-linked respiration when compared with LPP3 FL mice while body weight and global insulin sensitivity were similar between genotypes. Following HFD feeding, female LPP3 OE mice were protected from increased plasma LPA levels, excess adiposity, systemic insulin resistance, and systolic and diastolic cardiac dysfunction compared with LPP3 FL mice. Female LPP3 OE mice also maintained elevated cardiac pyruvate-linked mitochondrial respiration following HFD feeding while mitochondrial respiration was similar between genotypes in HFD-fed male mice. This study suggests that cardiomyocyte-specific LPP3 upregulation protects particularly female mice from HFD-induced metabolic dysfunction and cardiomyopathy. NEW & NOTEWORTHY Lipid phosphate phosphatase 3 (LPP3) hydrolyzes bioactive lipids including lysophosphatidic acid (LPA), elevated levels of which are implicated in obesity-induced metabolic and cardiac dysfunction. We show that cardiac-specific overexpression of LPP3 lowers plasma LPA levels, blunts LPA signaling in cardiomyocytes, and increases pyruvate-linked mitochondrial respiration in the heart at baseline in both male and female mice. In female mice, LPP3 overexpression also protects from high-fat diet-induced obesity, insulin resistance, and cardiac dysfunction.