The cGMP/PKG pathway as a common mediator of cardioprotection: translatability and mechanism

Abstract

Cardiomyocyte cell death occurring during myocardial reperfusion (reperfusion injury) contributes to final infarct size after transient coronary occlusion. Different interrelated mechanisms of reperfusion injury have been identified, including alterations in cytosolic Ca 2+ handling, sarcoplasmic reticulum-mediated Ca 2+ oscillations and hypercontracture, proteolysis secondary to calpain activation and mitochondrial permeability transition. All these mechanisms occur during the initial minutes of reperfusion and are inhibited by intracellular acidosis. The cGMP/PKG pathway modulates the rate of recovery of intracellular pH, but has also direct effect on Ca 2+ oscillations and mitochondrial permeability transition. The cGMP/PKG pathway is depressed in cardiomyocytes by ischaemia/reperfusion and preserved by ischaemic postconditioning, which importantly contributes to postconditioning protection. The present article reviews the mechanisms and consequences of the effect of ischaemic postconditioning on the cGMP/PKG pathway, the different pharmacological strategies aimed to stimulate it during myocardial reperfusion and the evidence, limitations and promise of translation of these strategies to the clinical practice. Overall, the preclinical and clinical evidence suggests that modulation of the cGMP/PKG pathway may be a therapeutic target in the context of myocardial infarction. LINKED ARTICLESThis article is part of a themed section on Conditioning the Heart -Pathways to Translation. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2015.172.issue-8 Abbreviations AMI, acute myocardial infarction; ANP, atrial natriuretic peptide; BH4, tetrahydrobiopterin; CaMK, Ca 2+ /calmodulin-dependent PK; eNOS, endothelial NOS; GIK, glucose-insulin-potassium; GLP-1, glucagon-like peptide-1; GSK3β, glycogen synthase kinase-3β; mPTP, mitochondrial permeability transition pore; NHE, Na+/H + exchanger; NP, natriuretic peptide; ODQ, 1H- [1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one; PCI, percutaneous coronary intervention; pGC, particulate GC; pHi, intracellular pH; PLB, phospholamban; PoCo, ischaemic postconditioning; PreC, ischaemic preconditioning; RIC, remote ischaemic conditioning; RISK, reperfusion injury salvage kinases; ROS, reactive oxygen species; SERCA, sarcoplasmic reticulum Ca Ischaemia/reperfusion injuryCardiomyocyte death is the main cause of the mortality and morbidity in patients with ischaemic heart disease, the leading cause of death in the global world population. It occurs mainly during the acute coronary syndrome, and in particular during myocardial infarction with ST-segment elevation, for which the main treatment is prompt reperfusion. There is solid evidence supporting that part of cell death, secondary to transient coronary occlusion, occurs upon restoration of coronary blood flow, a phenomenon known as reperfusion injury (Piper et al., 1998;Yellon and Hausenloy, 2007). The mechanisms responsible for cell death during myocardial reperfusion are complex but progressively better k...

The mitochondrial NO‐synthase/guanylate cyclase/protein kinase G signaling system underpins the dual effects of nitric oxide on mitochondrial respiration and opening of the permeability transition pore

“…However, according to the results presented by Seya and coauthors , S ‐nitrosoacetylpenacillamine (SNAP) or 8‐Bromo‐cGMP stimulated calcium‐dependent CytC release and apoptosis, while the inhibitors of NOS, GC, and PKG prevented these effects. These results contradict the generally admitted prosurvival action of cytosolic NOS/GC/PKG1 signaling system involved in the prevention of mPTP opening and cell death .…”

“…Mitochondrial permeability transition pore is considered as a common pathway leading to the development of apoptosis and necrosis, which are observed in myocardial ischemia/reperfusion (I/R) , acute steatohepatitis, and oxidative stress , and under the action of various drugs and toxins . Calcium and reactive oxygen species are recognized as key mediators involved in mPTP opening .…”

Bidirectional action of nitric oxide on mitochondrial respiration and permeability transition pore induced by calcium and palmitoylcarnitine

“…However, according to 4 the results presented by Seya and coauthors [23], SNAP or 8-Bromo-cGMP induced calciumdependent CytC release and apoptosis, while the inhibitors of NOS, GC, and PKG prevented these effects. These results contradict to the generally admitted pro-survival action of cytosolic NOS/GC/PKG1-SS directed at the prevention of MPTP opening and cell death [26][27][28][29].…”

“…MPTP is considered as a common pathway leading to the development of apoptosis and necrosis, which are observed in myocardial ischaemia-reperfusion (I/R) [28][29][30][31][32][33][34], acute steatohepatits and oxidative stress [31,35,36], and under the action of various drugs and toxins [31,37]. Calcium and reactive oxygen species (ROS) are recognized as key mediators involved in MPTP opening [31,32].…”

LncRNA SLC8A1‐AS1 protects against myocardial damage through activation of cGMP‐PKG signaling pathway by inhibiting SLC8A1 in mice models of myocardial infarction

“…Additionally, our experiment results revealed that upregulated SLC8A1‐AS1 exhibited notably elevated mRNA and protein levels of PKG1, PKG2, ANP, and BNP, indicating that the overexpression of SLC8A1‐AS1 could act to reversely downregulate the expression levels of genes related to the cGMP‐PKG pathway induced by SLC8A1 overexpression. Evidence has been presented suggesting that the cGMP/PKG pathway is a common mediator of cardioprotection and modulation of the cGMP/PKG pathway highlighting its potential as a therapeutic target for MI (Inserte & Garcia‐Dorado, ). A previous study provided verification indicating that the cGMP/PKG signaling pathway contributes to myocardial postconditioning protection to a certain degree (Inserte et al, ).…”