Novel Approaches and Opportunities for Cardioprotective Signaling Through 3′,5′-Cyclic Guanosine Monophosphate Manipulation

Limiting the injurious effects of myocardial ischemia-reperfusion is a desirable therapeutic target, which has been investigated extensively over the last three decades. Here we provide an up to date review of the literature documenting the experimental and clinical research demonstrating the effects of manipulating cGMP for the therapeutic targeting of the injurious effects of ischemic heart disease. Augmentation of the cyclic nucleotide cGMP plays a crucial role in many cardioprotective signaling pathways. There is an extensive body of literature which supports pharmacological targeting of cGMP or upstream activators in models of ischemia-reperfusion to limit injury. NO donors have long been utilised to manipulate cGMP, and more recently non-NO synthase derived NOx species have been investigated, resulting in their evaluation in clinical trials for the treatment of ischemic heart disease. Encouraging results demonstrate that natriuretic peptides are worthy candidates in manipulating cGMP and its downstream effectors to afford cytoprotection. Synthetic ligands have been designed which co-activate natriuretic peptide receptors to improve targeting this pathway. Advances have been made in targeting the soluble guanylyl cyclase which catalyzes the production of cGMP independently of the endogenous ligand NO using NO-independent stimulators and activators of sGC. These novel compounds show promise as a new class of drugs that target this signaling cascade specifically under pathological conditions when endogenous NO production may be compromised. Regulating the degradation of cGMP via phosphodiesterase inhibition also shows therapeutic potential. It is clear that production and regulation of cGMP is complex, indeed its spatial production and cellular distribution are only just emerging.