The mitochondrial regulator PGC1 alpha is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure

Phosphodiesterase 5 inhibition (PDE5i) activates cGMP-dependent protein kinase (PKG) and ameliorates heart failure; however, its impact on cardiac mitochondrial regulation has not been fully determined. Here, we investigated the role of the mitochondrial regulator peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC1 alpha) in the PDE5i-conferred cardioprotection, utilizing PGC1 alpha null mice. In PGC1 alpha(+/+) hearts exposed to 7 weeks of pressure overload by transverse aortic constriction, chronic treatment with the PDE5 inhibitor sildenafil improved cardiac function and remodeling, with improved mitochondrial respiration and upregulation of PGC1 alpha mRNA in the myocardium. By contrast, PDE5i-elicited benefits were abrogated in PGC1 alpha(-/-) hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1 alpha, while inhibition of the transcription factor CREB abrogated the PGC1 alpha induction. Together, these results suggest that the PKG-PGC1 alpha axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure.