Associate editor: M. MadhaniCyclic GMP signaling in cardiovascular pathophysiology and therapeutics
Introduction
Cyclic 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. In the cardiovascular system, cGMP signaling is vital to endothelial, vascular smooth muscle, and cardiac myocyte function. 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. Since the discovery of cGMP in rat urine nearly 50 years ago (Ashman et. al, 1963), the field of cGMP signaling research has grown exponentially. 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.
cGMP has two distinct pathways that regulate its synthesis, one coupled to natriuretic peptide hormone, and the other a simple gas (nitric oxide) (Fig. 1). No other second messenger, not even cyclic adenosine monophosphate (cAMP), is activated by a gas. 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, Katsuki et al., 1977, Schultz et al., 1977, Ignarro et al., 1987a, Ignarro et al., 1987b). 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 (de Bold, 1982, Ackermann et al., 1984, Atarashi et al., 1984, Atlas et al., 1984, Bloch et al., 1985, de Bold, 1985). 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.
Each of these pathways couples to a distinct guanylyl cyclase isoform — soluble (sGC) and particulate (pGC) guanylyl cyclase respectively. These cyclases differ in their intracellular distribution, with sGC historically described as a cytosolic protein and pGC being a membrane bound protein. However, their intracellular localization is more nuanced, and recent studies support distinct pools of cGMP generation with different downstream effects (Castro et al., 2006, Takimoto et al., 2007, Nausch et al., 2008). Cyclic GMP activates three types of effector molecules, with cGMP-dependent protein kinases (PKGs) and phosphodiesterases (PDEs) predominating in the cardiovascular system. A third type of effector molecule, cGMP-gated cation channels, exists in retinal and olfactory neuroepithelium and nephrons, but neither protein expression nor physiological function of these channels have been established in the cardiovascular system. Cyclic GMP-PKG signaling within the vascular endothelium stimulates cell proliferation and increases permeability (Draijer et al., 1995a, Draijer et al., 1995b, Vaandrager and de Jonge, 1996, Holschermann et al., 1997, Hood and Granger, 1998, Smolenski et al., 2000, Kook et al., 2003); it inhibits cell proliferation and mediates vasorelaxation in vascular smooth muscle (Archer et al., 1994, Bolotina et al., 1994, Cornwell et al., 1994, Murad et al., 1985); while in cardiac myocardium, it inhibits hypertrophy and modulates contractility (Lohmann et al., 1991, Shah et al., 1994, Takimoto et al., 2005b, Kinugawa et al., 1997, Vila-Petroff et al., 1999, Tatsumi et al., 2000). In all three tissues, cGMP-PKG signaling also mediates cellular apoptosis (Fukuo et al., 1996, Wu et al., 1997, DeMeester et al., 1998, Arstall et al., 1999, Suenobu et al., 1999, Taimor et al., 2000).
Lastly, cGMP catabolism is regulated by a subgroup of the 11 member phospho-diesterase superfamily. PDEs play a role in not only spatiotemporal regulation of cGMP signal but also cross-regulation of the cAMP signal. The strategy of inhibiting PDEs to enhance cGMP and related signaling has already been harnessed with the PDE5A inhibitor sildenafil, a common treatment for erectile dysfunction (Boolell et al., 1996). PDE inhibition has been further examined for the treatment of a variety of cardiovascular diseases, including pulmonary hypertension and now chronic heart failure, and this continues to be a highly active and promising field of research (Bethke et al., 1992a, Bethke et al., 1992b, Eddahibi et al., 1998, Gillies et al., 2002, Reffelmann and Kloner, 2003, Guazzi and Samaja, 2007, Lewis et al., 2007a, Attina et al., 2008, Baliga et al., 2008, Park, 2008).
This review summarizes our current understanding of cGMP signaling within the cardiovascular system, specifically in vascular endothelial and smooth muscle cells and cardiac myocytes. Several others have reviewed specific aspects of nitric oxide and natriuretic peptide, PKG, and PDE5 signaling (Kass et al., 2007a, Hofmann et al., 2009, Gillies et al., 2002, Saraiva and Hare, 2006, Rastaldo et al., 2007, Schulz et al., 2008, Woodard and Rosado, 2008). After discussing the major elements of the cGMP signaling pathway, we focus on the role of dysfunctional cGMP signaling in cardiovascular disease and the potential targets that this poses for the pharmacological treatment of cardiovascular diseases.
Section snippets
Generation by guanylyl cyclases
The biosynthesis of cyclic GMP from guanosine triphosphate (GTP) is catalyzed by two different isoforms of guanylyl cyclase, one which functions as the biosensor for nitric oxide and the other, as the plasma membrane receptor for natriuretic peptides.
Vascular smooth muscle cells
cGMP signaling directs vascular tone and smooth muscle cell (SMC) proliferation and differentiation (Fig. 3) (Murad et al., 1985, Munzel et al., 2003). Vascular tone is regulated by changes in intracellular free calcium concentrations within SMCs. In general, SMC contraction is triggered by the receptor-mediated generation of the second-messenger inositol 1,4,5-trisphosphate (IP3). IP3 induces release of free calcium from intracellular stores, further provoking influx of extracellular calcium
Pathophysiological role of cGMP signaling in cardiovascular disease
With cGMP signaling being as vital as it is to the physiologic functions of the heart and vasculature, it comes as no surprise that dysfunction at any level of the cGMP signaling pathway is a factor in many cardiovascular diseases. Endothelial cell dysfunction contributes to hypertensive disease, both systemic and pulmonary, and atherosclerosis; vascular smooth muscle dysfunction, systemic and pulmonary hypertensive and ischemic heart disease; and cardiac myocyte dysfunction, hypertrophic and
Pharmacologic modulation of cGMP signaling in cardiovascular disease
Given that cGMP signaling is dysregulated in a wide spectrum of cardiovascular diseases and can be altered at multiple levels, from upstream triggering events to downstream effectors and regulatory molecules, each step of the cascade becomes a promising target for pharmacologic therapy (Table 1).
Conclusions and perspectives
The central role of cGMP in mediating various physiological processes within the cardiovascular system presents this second messenger as a prime target for pharmacologic modulation. Many different approaches have been undertaken to enhance the cGMP signal. Supplementation with essential co-factors for eNOS can restore the bioavailability of NO in diseased states. NO-donor drugs and synthetic chimeric natriuretic peptides can trigger cGMP production through their respective guanylyl cyclases.
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