These cyclases differ in their intracellular distribution, with sGC historically described as a cytosolic protein and pGC being a membrane bound protein. PDE5 similarly increases its catalytic activity for cGMP by an order of magnitude upon cGMP binding to its regulatory GAF domain.Įach of these pathways couples to a distinct guanylyl cyclase isoform- soluble (sGC) and particulate (pGC) guanylyl cyclase respectively. Upon cGMP binding to its regulatory GAF domain, PDE2 undergoes a conformational change and increases its enzymatic activity for cAMP. PDE2 and PDE3 catabolize both cAMP and cGMP, whereas PDE5 specifically catabolizes cGMP. 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. cGMP can then activate cGMP-dependent protein kinase (PKG) and either activate (green arrow) or inhibit (red arrow bar) various phophodiesterase isoforms. cGMP is produced by particulate (pGC) and soluble (sGC) guanylyl cyclases, upon natriuretic peptide and nitric oxide activation, respectively. The discovery of atrial natriuretic peptide was momentous in its implication of the heart as more than a circulatory pump or electrically conductive tissue but also an endocrine organ a finding which ultimately helped shift the conceptual paradigm of heart failure to the current neurohormonal model.ĬGMP signaling cascade. Natriuretic peptide-mediated cGMP signaling was discovered in the early 1980s, when a polypeptide hormone was isolated from heart atrial muscle tissue and found to have potent diuretic (natriuretic) and hypotensive properties ( Ackermann et al., 1984 Atarashi et al., 1984 Atlas et al., 1984 Bloch et al., 1985 de Bold, 1982 de Bold, 1985). The significance of NO-cGMP signaling was recognized by the 1998 Nobel Prize in Physiology and Medicine that was awarded for the major discoveries surrounding nitric oxide ( Arnold et al., 1977 Ignarro et al., 1987a Ignarro et al., 1987b Katsuki et al., 1977 Schultz et al., 1977). No other second messenger, not even cyclic adenosine monophosphate (cAMP), is activated by a gas. Abnormalities at each step of the cGMP signaling cascade, from cGMP synthesis to its degradation, have been implicated in cardiovascular disease and thus represent potential targets for pharmacologic therapies.ĬGMP has two distinct pathways that regulate its synthesis, one coupled to natriuretic peptide hormone, and the other a simple gas (nitric oxide) ( Fig. al, 1963), the field of cGMP signaling research has grown exponentially. Since the discovery of cGMP in rat urine nearly 50 years ago (Ashman et. Generated by guanylyl cyclase isoforms in response to natriuretic peptides (NPs) and nitric oxide (NO), cGMP exerts its actions through cGMP-gated cation channels, cGMP-dependent protein kinases (PKGs), and cGMP-regulated phosphodiesterases (PDEs) that in turn hydrolyze cyclic nucleotides. In the cardiovascular system, cGMP signaling is vital to endothelial, vascular smooth muscle, and cardiac myocyte function. We detail the various therapeutic interventional strategies that have been developed or are in development, summarizing relevant preclinical and clinical studies.Ĭyclic guanosine 3′,5′-monophosphate (cGMP) is a ubiquitous intracellular second-messenger that mediates a vast array of physiologic processes, from ion channel conductance to cell growth and apoptosis to cellular mobility and contractility. 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. In addition, we illustrate how cGMP signaling becomes dysregulated in specific cardiovascular disease states. In this review, we outline each step of the cGMP signaling cascade and discuss its regulation and physiologic effects 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. Cyclic guanosine 3′,5′-monophosphate (cGMP) mediates a wide spectrum of physiologic processes in multiple cell types within the cardiovascular system.
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