Modulation of PPAR‐α and PPAR‐γ Influences Cardiomyocyte Growth and Cardiac Remodeling

ABSTRACT Peroxisome proliferator–activated receptors (PPARs), particularly PPAR‐α and PPAR‐γ, are key regulators of cardiac energy metabolism and have been implicated in cardiac remodeling. However, their roles in cardiomyocyte proliferation and hypertrophy remain incompletely understood. In this study, we investigated the effects of PPAR‐α and PPAR‐γ modulation on neonatal rat cardiomyocytes (NRCMs) using pharmacological agonists (WY‐14643 for PPAR‐α and pioglitazone for PPAR‐γ) and inhibitors (MK‐886 for PPAR‐α and GW9662 for PPAR‐γ), as well as siRNA‐mediated knockdown approaches. Cardiomyocyte proliferation and hypertrophy were assessed by immunofluorescence, cell size measurements, and proliferation assays. Our findings demonstrate that PPAR‐α activation significantly promotes cardiomyocyte proliferation and reduces hypertrophy, whereas PPAR‐α inhibition induces hypertrophic changes and suppresses proliferation. Similarly, PPAR‐γ activation enhances both proliferation and hypertrophy of cardiomyocytes, suggesting its involvement in physiological hypertrophy and a potential protective role in pathological remodeling. In contrast, pharmacological activation or genetic inhibition of PPAR‐δ showed no significant effects on cardiomyocyte proliferation or hypertrophy, highlighting its distinct role in metabolic homeostasis rather than structural remodeling. PPAR‐α and PPAR‐γ play distinct but complementary roles in regulating cardiomyocyte proliferation and hypertrophy. These results suggest that targeting PPAR‐α and PPAR‐γ may represent promising therapeutic strategies for cardiac hypertrophy and heart failure. Further in vivo studies are warranted to clarify their molecular mechanisms and potential clinical applications.