Journal Article

Cyclic GMP and protein kinase‐G in myocardial ischaemia‐reperfusion: opportunities and obstacles for survival signaling

Burley, D S, Ferdinandy, P, Baxter, G F

2007

Overview

It is clear that multiple signalling pathways regulate the critical balance between cell death and survival in myocardial ischaemia–reperfusion. Recent attention has focused on the activation of survival or salvage kinases, particularly during reperfusion, as a common mechanism of many cardioprotective interventions. The phosphatidyl inositol 3′‐hydroxy kinase/Akt complex (PI3K/Akt) and p42/p44 mitogen‐activated protein kinase cascades have been widely promoted in this respect but the cyclic guanosine 3′,5′‐monophosphate/cGMP‐dependent protein kinase (cGMP/PKG) signal transduction cassette has been less systematically investigated as a survival cascade. We propose that activation of the cGMP/PKG signalling pathway, following activation of soluble or particulate guanylate cyclases, may play a pivotal role in survival signalling in ischaemia–reperfusion, especially in the classical preconditioning, delayed preconditioning and postconditioning paradigms. The resurgence of interest in reperfusion injury, largely as a result of postconditioning‐related research, has confirmed that the cGMP/PKG pathway is a pivotal salvage mechanism in reperfusion. Numerous studies suggest that the infarct‐limiting effects of preconditioning and postconditioning, exogenously donated nitric oxide (NO), natriuretic peptides, phosphodiesterase inhibitors, and other diverse drugs and mediators such as HMG co‐A reductase inhibitors (statins), Rho‐kinase inhibitors and adrenomedullin, whether given before and during ischaemia, or specifically at the onset of reperfusion, may be mediated by activation or enhancement of the cGMP pathway, either directly or indirectly via endogenous NO generation downstream of PI3K/Akt. Putative mechanisms of protection include PKG regulation of Ca2+ homeostasis through the modification of sarcoplasmic reticulum Ca2+ uptake mechanisms, and PKG‐induced opening of ATP‐sensitive K+ channels during ischaemia and/or reperfusion. At present, significant technical obstacles in defining the precise roles played by cGMP/PKG signalling include the heavy reliance on pharmacological PKG inhibitors of uncertain selectivity, difficulties in determining PKG activity in intact tissue, and the growing recognition that intracellular compartmentalisation of the cGMP pool may contribute markedly to the nucleotide's biological actions and biochemical determination. Overall, the body of experimental evidence suggests that cGMP/PKG survival signalling ameliorates irreversible injury associated with ischaemia–reperfusion and may be a tractable therapeutic target. British Journal of Pharmacology (2007) 152, 855–869; doi:10.1038/sj.bjp.0707409; published online 13 August 2007

• Publisher: Blackwell Publishing Ltd,Nature Publishing Group
• Subject: Animals / Apoptosis - drug effects / Apoptosis - physiology / atrial natriuretic peptide / B‐type natriuretic peptide / Cardiotonic Agents - pharmacology / Cardiotonic Agents - therapeutic use / Cell Survival - drug effects / Cell Survival - physiology / cGMP‐dependent protein kinase / Cyclic GMP - physiology / Cyclic GMP-Dependent Protein Kinases - antagonists & inhibitors / Cyclic GMP-Dependent Protein Kinases - physiology / cyclic guanosine 3′,5′‐monophosphate / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / Humans / myocardial infarction / Myocardial Reperfusion Injury - enzymology / Myocardial Reperfusion Injury - metabolism / Myocardial Reperfusion Injury - physiopathology / Natriuretic Peptides - physiology / nitric oxide / nitric oxide synthase / particulate guanylate cyclase / Phosphodiesterase Inhibitors - pharmacology / Phosphodiesterase Inhibitors - therapeutic use / Reviews / Signal Transduction - physiology / soluble guanylate cyclase