Peroxisome Proliferator-Activated Receptor Family of Lipid-Activated Nuclear Receptors Alpha Silencing Promotes Oxidative Stress and Hypertrophic Phenotype in Rat Cardiac Cells

The peroxisome proliferator-activated receptor family of lipid-activated nuclear receptors (PPARs) plays a critical role in the regulation of cellular lipid metabolism. In cardiac muscle, PPARα is highly expressed and regulates genes involved in fatty acid oxidation, but its activity is downregulated in hypertrophic hearts. The functional role of PPARα in cardiac muscle has been investigated through the PPARA−/− mouse model, which, although having a normal life span, develops progressive cardiac fibrosis, but the consequences of chronic PPARα deficiency on the cardiac contractile apparatus remain unclear. To verify the PPARα role in hypertrophic phenotype, we generated an in vitro model of cardiac hypertrophy (CH) by stable silencing of PPARA gene in H9c2 rat cardiomyoblasts. We observed that PPARα silencing induces a hypertrophic phenotype, characterized by increased NPPB and decreased FBXO32 expression, mitochondrial dysregulation, impaired lipid metabolism, oxidative stress, and ferroptosis-related alterations. Epigenetically, H3K27ac levels increased while H3K27me3 decreased. Moreover, miR-34a, miR-132, and miR-331 were downregulated, implicating a miRNA-mediated mechanism in PPARα-linked cardiac hypertrophy. Treatment with Ebselen (Ebs), a redox-active compound with epigenetic inhibitory effects, reversed hypertrophic phenotype and restored miRNA levels. In conclusion, we found that PPARα depletion promotes oxidative stress and a hypertrophic phenotype and Ebs as a potential therapeutic agent.