Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics

Abstract

Cyclic guanosine 3',5'-monophosphate (cGMP) mediates a wide spectrum of physiologic processes in multiple cell types within the cardiovascular system. Dysfunctional signaling at any step of the cascade - cGMP synthesis, effector activation, or catabolism - have been implicated in numerous cardiovascular diseases, ranging from hypertension to atherosclerosis to cardiac hypertrophy and heart failure. In this review, we outline each step of the cGMP signaling cascade and discuss its regulation and physiologic effects within the cardiovascular system. In addition, we illustrate how cGMP signaling becomes dysregulated in specific cardiovascular disease states. The ubiquitous role cGMP plays in cardiac physiology and pathophysiology presents great opportunities for pharmacologic modulation of the cGMP signal in the treatment of cardiovascular diseases. We detail the various therapeutic interventional strategies that have been developed or are in development, summarizing relevant preclinical and clinical studies.

Figure 1

cGMP signaling cascade. cGMP is produced by particulate (pGC) and soluble (sGC) guanylyl cyclases, upon natriuretic peptide and nitric oxide activation, respectively. cGMP can then activate cGMP-dependent protein kinase (PKG) and either activate (green arrow) or inhibit (red arrow bar) various phophodiesterase isoforms. PKG-I phosphorylates several protein targets, including phospholamban (PLB), vasodilatory-stimulated phosphoprotein (VASP), regulator of G protein signaling 2 (RGS2), and the L-type calcium channel. PDE2 and PDE3 catabolize both cAMP and cGMP, whereas PDE5 specifically catabolizes cGMP. Upon cGMP binding to its regulatory GAF domain, PDE2 undergoes a conformational change and increases its enzymatic activity for cAMP. PDE5 similarly increases its catalytic activity for cGMP by an order of magnitude upon cGMP binding to its regulatory GAF domain.

Figure 2

Compartmentalization of cGMP signal. (A) NP-induced cGMP pool is subplasmalemmal and specifically hydrolyzed by the PDE2 isoform. In contrast, NO-induced cGMP pool appears to be more cytosolic, not localized to the subplasmalemmal region, and is specifically hydrolyzed by PDE5 isoform. (B) In studies of adeno-CNGA2 infected adult rat cardiac myocytes, Castro et al.(2006) measured the CNG channel current in response to ANP and the NO-donor SNAP in the presence of selective (EHNA for PDE2; sildenafil for PDE5) and non-selective (IBMX) PDE inhibitors. A hydrolysis-resistent cGMP analog (Sp-8) was used as the positive control. These findings established the specificity of PDE2 and PDE5 for the distinct NP-cGMP and NO-cGMP pools, respectively. (C) Summary data of contractility studies of intact mouse hearts by Takimoto et al. (2007) demonstrated that the β-adrenergic response is modulated specifically by the NO-cGMP signal pool. These studies established that the distinct cGMP pools have distinct functions. (ISO, isoproterenol; Sil, sildenafil; ANP, atrial natriuretic peptide)

Figure 3

Physiological effects of cGMP-PKG activation in various cell types of the cardiovascular system.

Figure 4

Dysfunctional cGMP signaling in cardiovascular diseases.