Protein Kinase G I and Heart Failure

Abstract

The cyclic GMP (cGMP) signaling pathway is a ubiquitous second messenger system that regulates diverse cellular functions. The cGMP-dependent protein kinase G (PKG) is a primary direct cGMP effector in multiple cell types. cGMP-PKG signaling plays critical roles throughout the cardiovascular system, although the best understood function of PKG is as an inducer of vascular smooth muscle relaxation, leading to arteriolar vasodilation (see Munzel et al1 for an extensive review on the subject). However, during the past decade, multiple studies have revealed important functions of cGMP and PKG signaling in the myocardium, and particularly in the attenuation of pathological cardiac hypertrophy and remodeling. This has created great interest in targeting this pathway to treat heart failure. Multiple cGMP-generating compounds have now been investigated for the treatment of heart failure. Although these agents target different upstream components of the cGMP pathway, they all ultimately function as PKG I (PKGI) activators (Figure). Because of the rapid induction by PKG of vascular relaxation, most clinical trials to date have studied these agents in acute decompensated heart failure (ADHF). However, more recent clinical studies, informed by basic data, have begun to explore a role for these agents as chronic myocardial antiremodeling therapies, which, ironically, are being limited in many cases by undesired excessive vasodilation and hypotension resulting from PKG activation in the vasculature. Figure. Summary of PKGI activation pathway in cardiovascular tissues. Currently available pharmacological agents targeting specific components of the pathway are shown in red. Also represented are the hypothesized overlapping, but nonidentical, protein kinase G I (PKGI) substrates in the vascular smooth muscle cell and cardiac myocyte, which may mediate vasodilation and attenuation of cardiac remodeling, respectively. ANP indicates atrial natriuretic peptide; BNP, B-type natriuretic peptide; LZ, leucine zipper domain; NEP, neutral endopeptidase (neprilysin); pGC, particulate guanylate cyclase (NP receptor); and sGC, …