The role of gasotransmitters NO, H₂S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

Abstract

Ischaemic heart disease is one of the leading causes of morbidity and mortality worldwide. The development of cardioprotective therapeutic agents remains a partly unmet need and a challenge for both medicine and industry, with significant financial and social implications. Protection of the myocardium can be achieved by mechanical vascular occlusions such as preconditioning (PC), when brief episodes of ischaemia/reperfusion (I/R) are experienced prior to ischaemia; postconditioning (PostC), when the brief episodes are experienced at the immediate onset of reperfusion; and remote conditioning (RC), when the brief episodes are experienced in another vascular territory. The elucidation of the signalling pathways, which underlie the protective effects of PC, PostC and RC, would be expected to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent reperfusion injury. Gasotransmitters including NO, hydrogen sulphide (H2S) and carbon monoxide (CO) are a growing family of regulatory molecules that affect physiological and pathological functions. NO, H2S and CO share several common properties; they are beneficial at low concentrations but hazardous in higher amounts; they relax smooth muscle cells, inhibit apoptosis and exert anti-inflammatory effects. In the cardiovascular system, NO, H2S and CO induce vasorelaxation and promote cardioprotection. In this review article, we summarize current knowledge on the role of the gasotransmitters NO, H2S and CO in myocardial I/R injury and cardioprotection provided by conditioning strategies and highlight future perspectives in cardioprotection by NO, H2S, CO, as well as their donor molecules. LINKED ARTICLESThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx. Abbreviations 3MP, 3-mercaptopyruvate; 3-MST, 3-mercaptopyruvate transferase; BCA, cyano-L-alanine; CBS, cystathionine β-synthase; CHD, coronary heart disease; CK, creatinine kinase; CORM, carbon monoxide-releasing molecule; CSE, cystathionine γ-lyase; CyPD, cyclophilin D; HPDTT, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione; eNOS, endothelial nitric oxide synthase; FeTPPS, 5,10,15, porphyrinato iron; GYY4137, morpholin-4-ium 4-methoxyphenyl-morpholino-phosphinodithioate; HNO, nitroxyl; HO, haem oxygenase; I/R, ischaemia/reperfusion; iNOS, inducible nitric oxide synthase; L-NAME, N-nitro-L-arginine methylester; L-NNA, Nω-nitro-l-arginine; LV, left ventricular; MitoSNO, mitochondria-targeted S-nitrosothiols; mPTP, mitochondria permeability transition pore; nNOS, neuronal nitric oxide synthase; Nrf2, nuclear factor (erythroid-derived 2)-like 2; NSAIDs, non-steroidal antiinflammatory drugs; ONOO − , peroxynitrite; PRG, DL-propargylglycine; PC, preconditioning; PostC, postconditioning; RC, remote conditioning; RISK, reperfusion injury salvage kinase; ROS, reactive oxygen species; SAC, S-allylcysteine; SAFE, survivor activating factor enhancement; SOD, superoxide dismutase; XOR, xanthin...

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…Experimental studies suggest that ischemic postconditioning prevents myocardial reperfusion injury and limits infarct size by inhibiting MPTP opening (Argaud et al, 2005). As with ischemic preconditioning, the mechanism through which this is achieved is not clear, but a number of potential signaling pathways have been proposed: 1) the activation of the prosurvival cardioprotective pathways, such as the RISK, SAFE, and NO-cGMP-PKG pathways, at the onset of reperfusion inhibit MPTP opening (Hausenloy et al, 2005Bopassa et al, 2006;Heusch et al, 2008Heusch et al, , 2011Boengler et al, 2011a;Andreadou et al, 2014); 2) the delayed restoration in intracellular pH may inhibit MPTP opening (Cohen et al, 2007); and 3) the reduction in ROS generated at reperfusion may prevent MPTP opening (Clarke et al, 2008).…”

“…Some of these agents have been investigated in the clinical setting already. The most promising pharmacologic cardioprotective agents and their potential targets include: cyclosporine-A (MPTP inhibition); metoprolol, matrix metalloproteinase (MMP) inhibition, glucagon-like peptide 1 (GLP-1) analogs (RISK pathway); and nitrite/nitrates and soluble guanylate cyclase activators (NO-cGMP-PKG pathway) (reviewed in Evgenov et al, 2006;Stasch et al, 2011;Sharma et al, 2012;Andreadou et al, 2014;Bice et al, 2014;Rassaf et al, 2014).…”

“…Pharmacologic Cardioprotection in Hyperlipidemia: Implications for Target Validation. One of the most extensively investigated cardioprotective cellular signaling pathways is the NO-cGMP-PKG pathway, and elements of this signaling pathway are thought to be promising drug targets (Burley et al, 2007;GarciaDorado et al, 2009;Gorbe et al, 2010;Andreadou et al, 2014;Bice et al, 2014). However, Giricz et al (2009) showed that, although the NO donor SNAP, which activates soluble guanylate cyclase, or BNP, which activates particulate guanylate cyclase, or the stable cGMP analog 8-bromo cGMP, significantly reduced infarct size in normal rat hearts, none of these treatments was effective in hearts of rats fed a cholesterolenriched diet.…”

350 años de la medicina hiperbárica: aspectos históricos, fisiopatogénicos y terapéuticos

“…Otro mecanismo por el cual el tratamiento en la cámara hiperbárica favorece la curación de las lesiones por isquemia-reperfusión es que amplifica los gradientes de oxígeno en la periferia de las heridas isquémicas y con ello promueve la angiogé-nesis, la cual requiere la formación de matriz de colágena, misma que a su vez es dependiente del oxí-geno. Finalmente, la terapia con oxígeno hiperbárico permite la redistribución del flujo sanguíneo debido a las diferencias en los gradientes, y por ello alivia el edema que se genera en los tejidos dañados, con lo cual se reduce el dolor y se mejora la función [19][20][21][22][23] . Es principalmente por las leyes físicas aquí expuestas, y las vías fisiológicas y fisiopatológicas involucradas, que la medicina hiperbárica ofrece beneficios para los problemas de salud que involucran dichas vías.…”

Specific Mechanisms Underlying Right Heart Failure: The Missing Upregulation of Superoxide Dismutase-2 and Its Decisive Role in Antioxidative Defense

“…To what extent the increased formation of ONOO -in the RV of the LC group influences structural or functional remodeling cannot be determined based on the current data. Furthermore, the significance of ONOO -as an exclusively harmful compound is in doubt, and its involvement in the maintenance of the redox homeostasis and stress adaptation is the subject of ongoing discussion (3,19,20).…”