Anti-Apoptotic and Anti-Inflammatory Effects of Hydrogen Sulfide in a Rat Model of Regional Myocardial I/R

Abstract

Hydrogen sulfide (H2S) is a novel gaseous mediator produced by cystathionine-beta-synthase and cystathionine-gamma-lyase in the cardiovascular system, including the heart. Using a rat model of regional myocardial ischemia/reperfusion, we investigated the effects of an H2S donor (sodium hydrogen sulfide [NaHS]) on the infarct size and apoptosis caused by ischemia (25 min) and reperfusion (2 h). Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by NaHS. Specifically, we demonstrate that NaHS (1) attenuates the increase in caspase 9 activity observed in cardiac myocytes isolated from the area at risk (AAR) of hearts subjected in vivo to regional myocardial I/R and (2) ameliorates the decrease in expression of Bcl-2 within the AAR obtained from rat hearts subjected to regional myocardial I/R. The cardioprotective effects of NaHS were abolished by 5-hydroxydeconoate, a putative mitochondrial adenosine triphosphate-sensitive potassium channel blocker. Furthermore, NaHS attenuated the increase in the I/R-induced (1) phosphorylation of p38 mitogen-activated protein kinase and Jun N-terminal kinase, (2) translocation from the cytosol to the nucleus of the p65 subunit of nuclear factor-kappaB, (3) intercellular adhesion molecule 1 expression, (4) polymorphonuclear leukocyte accumulation, (5) myeloperoxidase activity, (6) malondialdehyde levels, and (7) nitrotyrosine staining determined in the AAR obtained from rat hearts subjected to regional myocardial I/R. In conclusion, we demonstrate that the cardioprotective effect of NaHS is secondary to a combination of antiapoptotic and anti-inflammatory effects. The antiapoptotic effect of NaHS may be in part due to the opening of the putative mitochondrial adenosine triphosphate-sensitive potassium channels.

Hydrogen sulfide treatment improves long-term renal dysfunction resulting from prolonged warm renal ischemia-reperfusion injury

“…Multiple studies have demonstrated that H 2 S is capable of limiting leukocyte migration, and cytokine expression and release. [22][23][24][30][31][32] We found that H 2 S treatment during warm IRI initially decreased the expression of pro-inflammatory markers, increased the expression of pro-survival marker Bcl-2 and decreased the expression of pro-apoptotic marker BID. While the expression of these markers decreased toward Hydrogen sulfide treatment and long-term renal dysfunction baseline by day 7, H 2 S treatment also resulted in decreased long-term renal inflammation as evidenced by the diminished numbers of infiltrating macrophages in H 2 S treated kidneys at day 7.…”

“…[15][16][17][18] More recently, H 2 S has been shown to be protective in many models of tissue IRI, including brain, intestine, lung, liver and myocardium via a variety of antioxidant, anti-apoptotic and anti-inflammatory effects. [19][20][21][22][23] Using a rodent model of warm renal IRI involving uninephric renal clamping with clinically relevant, prolonged warm ischemic times, we have found that exogenous H 2 S treatment during warm renal IRI improves renal function and reduces IRIinduced inflammation in the acute recovery period. 24 To improve clinical outcomes following PN, H 2 S treatment must be shown to provide long-term improvement of renal function and resolution of inflammation.…”

The cardioprotective potential of hydrogen sulfide in myocardial ischemia/reperfusion injury (Review)

“…These channels are present in the cellular and mitochondrial membrane and open in the presence of H 2 S, mediating negative inotropic effect in the myocardium. These channels are also responsible -at least in part -for the vasodilatory effect of H 2 S. Blocking the channels either in the inner mitochondrial membrane (42) or in the sarcolemma (28) abolishes the cardioprotective effects. Besides the effect on K ATP channels, H 2 S inhibits L-type Ca 2+ channels in myocytes (7) via an unknown mechanism.…”

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

“…16,17 Different intracellular signaling pathways produce a combination of anti-apoptotic and anti-inflammatory effects based on the inhibition of caspase 9, p38 MAPK and c-Jun N-terminal kinase (JNK) activation, as well as of NF-kB nuclear traslocation and leukocyte accumulation in infarct areas. 18 Recently, however, it has been reported that in pancreatic acinar cells the activation of ERKs promotes cell survival, whereas the activation of JNKs and p38 MAPK leads to H 2 S-induced apoptosis. 19 We have shown that NaHS promotes the survival of cultured granulocytes: the delayed onset of granulocytes apoptosis in the presence of H 2 S is mediated by the inhibition of caspase-3 cleavage and p38 phosphorylation.…”