Contributor: Elise Vo

Precision therapy for HF is on the horizon. Activating cyclic guanosine monophosphate (cGMP)-dependent protein kinase-1α (PKG1α), results in vasodilation and prevents cardiac remodeling — a good thing. There are two ways to activate PKG1a: 1) directly soluble guanylate cyclase (sGC) activators and 2) indirectly by PDE5 inhibition. So, do these two methods of targeting PKG1α work equally well? Nakamura et al used a TAC murine model to demonstrate that the oxidative state of PKG1α determines whether or not sildenafil is efficacious in preventing pathologic remodeling in pressure-overload HF.


Cyclic GMP (cGMP) is synthesized by sGC in the cytosol while PDE5 catabolizes cGMP. Once synthesized, cGMP directly activates PKG1α, causing vasodilation through vascular smooth muscle cell substrates and cardiac remodeling via cardiac myocyte substrates. PKG1α can be oxidized at cysteine 42 residues to form a disulfide bond between homo-dimer subunits, PKG1α-42. PKG1α-42 oxidation decreased the enzyme’s ability to prevent pathologic remodeling in ischemic heart disease.

OK, so oxidation state of PKG1α matters. To determine whether efficacy of PDE5 inhibition and sGC stimulation depended on the oxidation state of PKG1α, PKG1α wild type (WT) and Knock-in mice expressing redox-dead PKG1α-42 went through 3 weeks of pressure overload from trans-aortic constriction (TAC). Drug treatment were randomized to PDE5-inhibitor (sildenafil) vs. sGC-activator (BAY602770). The results showed that in WT mice, both sildenafil and BAY602770 reduce hypertrophy (-51% vs. -58%, respectively, both p<0.0001). However, in fixed oxidation PKG1α-42 mice, sildenafil did not reduce heart mass (+5%, p=NS), but BAY602770 continued to reverse hypertrophy (-35%, p<0.03).

What causes sGC activation to be more effective than PDE5 inhibition in reducing heart mass when oxidation state is fixed? In WT mice, sildenafil increases cGMP by inhibiting PDE5, thereby preventing cGMP disintegration and causing PKG1α oxidation – and this oxidation step appears to be necessary for the drug’s effect to ameliorate pathologic remodeling from pressure-overload HF. In the PKG1α-42 mice, oxidation is fixed by the redox-resistant C42 residues; hence sildenafil renders no effects.

No study is perfect. The study is limited by the small experimental animal population, and of course, murine models may not correlate to human myocardial responses.

In a heartbeat… the study showed that the effect of sildenafil, an PDE5 inhibitor is dependent on the redox state of the cardiac cells, specifically PKG1α. This may explain different effects of drugs acting on the PKG1α system. SGC-activating drugs are currently in clinical trials in heart failure. Further study on PDE5 inhibitors in heart failure should take into consideration the myocardium oxidative stress state.

Study Link: Prevention of PKG-1α Oxidation Suppresses Antihypertrophic/Antifibrotic Effects From PDE5 Inhibition but not sGC Stimulation