Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: Opportunities and obstacles for survival signaling

D. S. Burley, P. Ferdinándy, G. F. Baxter

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

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 Ca 2+ homeostasis through the modification of sarcoplasmic reticulum Ca 2+ 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.

Original languageEnglish
Pages (from-to)855-869
Number of pages15
JournalBritish Journal of Pharmacology
Volume152
Issue number6
DOIs
Publication statusPublished - Nov 2007

Fingerprint

Guanylate Kinases
Cyclic GMP-Dependent Protein Kinases
Myocardial Reperfusion
Cyclic GMP
Reperfusion
Myocardial Ischemia
Ischemia
Phosphotransferases
Phosphatidylinositols
Nitric Oxide
Guanosine Monophosphate
Adrenomedullin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
rho-Associated Kinases
Natriuretic Peptides
Critical Pathways
Phosphodiesterase Inhibitors
Guanylate Cyclase
Mitogen-Activated Protein Kinase 1
Sarcoplasmic Reticulum

Keywords

  • Atrial natriuretic peptide
  • B-type natriuretic peptide
  • CGMP-dependent protein kinase
  • Cyclic guanosine 3′,5′-monophosphate
  • Myocardial infarction
  • Nitric oxide
  • Nitric oxide synthase
  • Particulate guanylate cyclase
  • Soluble guanylate cyclase

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion : Opportunities and obstacles for survival signaling. / Burley, D. S.; Ferdinándy, P.; Baxter, G. F.

In: British Journal of Pharmacology, Vol. 152, No. 6, 11.2007, p. 855-869.

Research output: Contribution to journalArticle

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