Cardiovascular cGMP-Generating Systems in Physiological and Pathological Conditions

Abstract

The intracellular messenger cyclic GMP (cGMP) represents the key signal in several transduction pathways throughout the animal world. In the heart cGMP signaling contributes to functional interaction of different cell types. Nitric oxide (NO) and natriuretic peptides (NPs), major autocrine-paracrine cardiovascular regulators, increment intracellular cGMP through guanylate cyclases (GCs). NO and NPs interact with two GC types: cytosolic (soluble: sGC) and membrane bound [particulate: pGC (NP receptor types A and B)], respectively. Depending on sub-cellular localization and regulation of the enzymes, cGMP produced by either pGC or sGC exerts different complementary effects. The two pathways are reciprocally regulated. NPs-depending pGC is modulated by NO-cGMP signaling, and the activity of NO is influenced by cellular concentrations of both NO itself and NPs. This heterologous feedback regulates GCs, linking cardiovascular autocrine-paracrine activities of NPs and NO. Importance of these cGMP converging routes goes far beyond their role under normal conditions. They are of relevance especially in disease states when tissue and circulating levels of NPs, and local NO production are altered. An example is the endothelial dysfunction associated with deficient NO production and uncoupled endothelium-myocardium communications. In this case, NPs-pGC-cGMP could supplement the reduced activity of NO-scGC-cGMP pathway. In addition, these systems regulate cell growth and apoptosis, playing a role in myocardial pathological morpho-functional remodeling. Here we will review recent concepts on NO/NPs dependent control of heart function in vertebrates, also focusing on cGMP-activated downstream signaling and its role in health and disease conditions.

Catecholamines, cardiac natriuretic peptides and chromogranin A: evolution and physiopathology of a ‘whip-brake’ system of the endocrine heart

“…These receptors, present from cyclostomes to mammals [for references, see Takei and Hirose (Takei and Hirose, 2002), Toop and Donald (Toop and Donald, 2004) and Garg and Pandey (Garg and Pandey, 2005)], conserve molecular and functional features. NPRA and NPRB are singlespanning transmembrane receptors, belonging to the family of particulate guanylate cyclases (pGC) [for references, see Cerra and Pellegrino (Cerra and Pellegrino, 2007)]. They show different affinities for ANP, BNP and CNP.…”

“…Moreover, fewer receptors are present in the septal side than in the free wall of the left ventricular EE (Kim et al, 1999). This compartmentalization provides the various heart regions with different abilities to bind NP and is essential for normal cardiac function, as regional alterations of NPR expression associate with a deteriorated heart performance [for references, see Cerra and Pellegrino (Cerra and Pellegrino, 2007)]. For example, NPR expressed in the ventricular EE (Wilcox et al, 1991;Rutherford et al, 1992) disappear in the presence of right ventricular hypertrophy (Kim et al, 1999), impairing EE-myocardium communications and thereby affecting contractility and contributing to cardiac damage.…”

“…Once released, NP elicit endocrine/paracrine/autocrine actions on a large number of proximal and distal targets, generating a complex multilevel network that controls heart-vessel and blood volume-ion homeostasis [for references, see Cerra and Pellegrino (Cerra and Pellegrino, 2007)]. This network orchestrates direct chronotropic, inotropic and potent vasorelaxant responses and indirect actions that minimize cardiac hemodynamic loads.…”

“…They decrease shear stress and modulate coagulation and fibrinolysis, thus preventing endothelial dysfunction. They also inhibit platelet activation, inflammation and abnormal growth, an action mainly exerted by CNP, which appears to counterbalance vascular remodeling [for references, see Cerra and Pellegrino (Cerra and Pellegrino, 2007)]. All these actions are exerted in concert with NO, prostaglandins and other vasodilator peptides and contribute to counteract the sodium-retaining, vasoconstrictive, thrombophylic, proinflammatory and prohypertrophic actions elicited by other stress-activated hormonal systems, such as the RAS.…”

“…Note the potentiation of cGMP signaling sustained by the NPRC-mediated inhibition of cAMP production. At the same time, the high amounts of cGMP generated close to the membrane feed back on pGC and on the membrane-associated sGC*, inhibiting enzyme activity and limiting cGMP production [see Cerra and Pellegrino (Cerra and Pellegrino, 2007) for references]. This feedback may be either homologous (e.g.…”