cGMP
Nucleotides and their Derivatives

The physiological effects of natriuretic peptides are elicited through three classes of cGMP binding proteins: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. Members of the natriuretic peptide family, atrial natriuretic peptide (ANP), brain natriuretic peptide, and C type natriuretic peptide, serve as physiological regulators of homeostasis including control of fluid retention and blood pressure. Clinical treatment of various cardiovascular pathologies shows that natriuretic peptides exert beneficial effects in arterial hypertension, myocardial infarction , coronary artery disease, and chronic heart failure. Collectively, these results suggest that ANP is cardioprotective.

Antiapoptotic effects of natriuretic peptide are mediated via activation of particulate guanylyl cyclases (pGCs) that modify GTP to elevate intracellular cGMP levels. Increases in cardiac cGMP levels inhibit ischemia/reperfusion damage by activation of the Akt/Bad/Bcl2 signaling pathway that prevents apoptotic cell death. Protective effects of cGMP may involve downstream activation of cGMP-dependent PKG, expressed in cardiomyocytes as the PKG I (but not PKG II) isoform, since PKG activates PI3K/Akt kinase signaling in vascular smooth muscle and endothelial cells. The ANP/cGMP/PKG signaling cascade is well known for antiapoptotic activity in neuronal cell types but is relatively unstudied in cardiomyocytes. However, ANP-induced cGMP signaling could certainly promote antiapoptotic responses in cardiomyocytes via Akt activation, since the protective effects of Akt in the myocardium are well known.
ANP exerted opposing effects upon cell survival depending upon concentration that could be related to the intensity of cGMP-dependent signaling activity initiated by ANP. Effects of varying cGMP concentrations upon apoptotic cell death were assessed by TUNEL assay using cultured cardiomyocytes. Treatment with cell-permeant cGMP produced significantly differing effects based upon concentration. cGMP at a low concentration was antiapoptotic, protecting cardiomyocytes from the staurosporine challenge; In contrast, a higher dose of cGMP alone was ineffective.