Chronic inhibition of cGMP-specific phosphodiesterase 5 attenuates myocardial hypertrophy by promoting mitophagy in cardiomyocytes

Cardiac hypertrophy is a pathological adaptive response to chronic hemodynamic stress or injury, which may progress irreversibly to heart failure if left untreated. The objective of the study was to investigate whether inhibition of phosphodiesterase 5 can induce mitophagy to alleviate pathological cardiac hypertrophy. Sildenafil (Sif) effectively alleviates isoproterenol-induced cardiac hypertrophy in vivo by decreasing left ventricular wall thickness, reducing cardiac interstitial fibrosis, and improving cardiac functional parameters. Additionally, Sif protects against cardiomyocyte hypertrophy in vitro by lowering atrial natriuretic peptide levels and cardiomyocyte cross-sectional area. It also enhances mitochondrial function through the activation of PTEN-induced putative kinase-1 (PINK1)/Parkin-mediated mitophagy. Importantly, the autophagy inhibitor chloroquine abolished Sif-induced mitophagy and cardioprotection, thereby confirming the essential role of autophagic flux. Furthermore, the protective effects of Sif were reversed by the protein kinase G (PKG) inhibitor KT5823, indicating a dependence on the cyclic GMP (cGMP)-PKG signaling pathway. Altogether, Sif enhances mitophagy and maintain mitochondrial integrity by activating the PINK1/Parkin pathway through the cGMP-PKG signaling cascade, highlighting its potential to protect the myocardium perioperatively.