Molecular Evidence That PKGI Inhibits Pathological Cardiac Hypertrophy and Remodeling Overview of PKGI Activation in the Cardiovascular System

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. cGMPPKG 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 Münzel et al 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. The purpose of this review, therefore, is 3-fold. First, we will review the upstream PKGI activation pathways. Second, we will examine the basic science studies that revealed the antiremodeling function of this pathway, both in isolated cardiac myocytes (CMs) and in vivo. Third, we will review the heart failure clinical trials of PKG activating agents, both in ADHF and also as emerging chronic antiremodeling therapies. Throughout, we will focus on the evidence from basic and clinical studies supporting exploration of CM-specific PKGI substrates that might serve as novel antiremodeling therapeutic targets to circumvent the undesired hypotension resulting from PKGI-induced vasodilation. Molecular Evidence That PKGI Inhibits Pathological Cardiac Hypertrophy and Remodeling Overview of PKGI Activation in the Cardiovascular System The Figure outlines the cGMP/PKG signaling pathway. cGMP is synthesized by guanylate cyclase (GC), either in the form of soluble GC (sGC) or particulate GC (pGC). sGC and pGC are in turn activated by upstream NO or natriuretic peptides (NP), respectively. As the names imply, sGC resides in the cytosol, where it is stimulated by NO diffusing directly across the plasma membrane. pGC, on the contrary, is a membranebound receptor (also termed the NP receptor) activated by extracellular NPs, including atrial NP and B-type NP (BNP). NP activation of pGC induces cGMP synthesis on the inner plasma membrane. Phosphodiesterases (PDEs), which catabolize cGMP, provide a second layer of regulation of intracellular cGMP levels. At least 9 PDEs exist in the cardiovascular system. Most of the PDEs catabolize both cGMP and cAMP, although cGMPselective PDEs, such as PDE5, also exist. cGMP also inhibits PDE5 in a negative feedback manner. cGMP directly activates a number of molecules, including PDEs and ion channels. However, PKGI represents the best characterized cGMP downstream signaling effector. Two PKG genes, PKGI and PKGII, exist but only PKGI is expressed in the cardiovascular system, and this review therefore focuses on PKGI. The PKGI gene expresses as 2 separate isoforms: PKGIα and Iβ, which are splice variants of the same gene and differ only in sequence of their N-terminal leucine zipper (LZ) interaction domain. These LZ domains mediate PKGI binding to specific substrates, many of which contain similar LZ domains, thus allowing LZ–LZ cointeraction. The difference in sequence between the Iα and Iβ LZ domains permits these different isoforms to interact with and phosphorylate unique sets of kinase substrates. As we will describe, much of our understanding of the role of these kinases in the