Nitric Oxide-cGMP-PKG Signaling in the Cardioprotective Effects of Phosphodiesterase 5 Inhibitors

Phosphodiesterase 5 (PDE5) is an enzyme that catalyzes the degradation of cGMP to its inactive form, 5′-GMP. The inhibition of PDE5 leads to the increase in bioavailability of cGMP which exerts its downstream signaling effects through the activation of protein kinase G (PKG). The dysregulation of cGMP-PKG signaling cascade plays a critical role in the pathology of several cardiovascular disorders. PDE5 inhibitors including sildenafil and tadalafil are widely prescribed drugs for the treatment of erectile dysfunction and pulmonary hypertension in patients. In the pre-clinical setting, treatment with PDE5 inhibitors protect against several cardiovascular pathologies including ischemia/reperfusion (I/R) injury, heart failure, pressure overload-induced hypertrophy, and cardiomyopathy associated with type 2 diabetes and metabolic syndrome. Mechanistic studies reveal that nitric oxide (NO)-cGMP-PKG signaling driven multiple signaling pathways are involved in protection against most of these pathologies. Moreover, the PDE5 inhibitors generate other gasotransmitters including hydrogen sulfide, carbon monoxide in addition to NO that may play a critical role in cardioprotection.