Cardiomyocyte peroxisome proliferator-activated receptor prevents septic cardiomyopathy via improving mitochondrial function

Clinically, cardiac dysfunction is a key component of sepsis-induced multi-organ failure. Mitochondria are essential for cardiomyocyte homeostasis, as disruption of mitochondrial dynamics enhances mitophagy and apoptosis. However, therapies targeted to improve mitochondrial function in septic patients have not been explored. Transcriptomic data analysis revealed that the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the heart was the most significantly decreased in the cecal ligation puncture-treated mouse heart model, and PPARa was the most notably decreased among the three PPAR family members. Male Ppara(fl/fl) (wild-type), cardiomyocyte-specific Ppara-deficient (Ppara(?CM)), and myeloid-specific Ppara-deficient (Ppara(?Mac)) mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxic cardiac dysfunction. PPARa signaling was decreased in LPS-treated wild-type mouse hearts. To determine the cell type in which PPARa signaling was suppressed, the cell type-specific Ppara-null mice were examined. Cardiomyocyte- but not myeloid-specific Ppara deficiency resulted in exacerbated LPS-induced cardiac dysfunction. Ppara disruption in cardiomyocytes augmented mitochondrial dysfunction, as revealed by damaged mitochondria, lowered ATP contents, decreased mitochondrial complex activities, and increased DRP1/MFN1 protein levels. RNA sequencing results further showed that cardiomyocyte Ppara deficiency potentiated the impairment of fatty acid metabolism in LPS-treated heart tissue. Disruption of mitochondrial dynamics resulted in increased mitophagy and mitochondrial-dependent apoptosis in Ppara(?CM) mice. Moreover, mitochondrial dysfunction caused an increase of reactive oxygen species, leading to increased IL-6/STAT3/NF-?B signaling. 3-Methyladenine (3-MA, an autophagosome formation inhibitor) alleviated cardiomyocyte Ppara disruption-induced mitochondrial dysfunction and cardiomyopathy. Finally, pre-treatment with the PPARa agonist WY14643 lowered mitochondrial dysfunction-induced cardiomyopathy in hearts from LPS-treated mice. Thus, cardiomyocyte but not myeloid PPARa protects against septic cardiomyopathy by improving fatty acid metabolism and mitochondrial dysfunction, thus highlighting that cardiomyocyte PPARa may be a therapeutic target for the treatment of cardiac disease.