Physiological role of H2S in cardiovascular system
Vasodilation
H2S is emerging as a novel and an important physiological mediator in the cardiovascular system.
Reports of ‘cross-talk’ between H2S and NO in the regulation of vascular endothelium show mixed results. H2S is reported to act synergistically with NO to mediate vasodilation. It is well-known that NO has direct vasodilator, anti-thrombotic, anti-inflammatory and anti-proliferative effects in the cardiovascular system. It was found that NO-induced vasodilation was enhanced by exogenously administrated SNP, an NO donor, which increased the synthesis of H2S in both vascular tissues and organs. Numerous mechanisms have been proposed by which H2S moderates vascular tone. Some authors have reported that H2S mediates vasorelaxation through the opening of ATP-sensitive potassium (KATP) channels in the smooth muscle. These channels are mainly composed of the pore-forming Kir6.1 subunit and regulatory sulfonylurea receptor 1 (SUR1) subunit. H2S binds to cysteine residues of the extracellular loop of SUR1, changes the configuration of KATP channel complex and then results the open of Kir6.1 and enhancements of KATP currents. Other vasorelaxant mechanisms have also been identified. Jackson-Weaver et al. demonstrated that H2S dilates mesenteric arteries by activating endothelial large-conductance Ca2+- activated potassium channels and smooth muscle Ca2+ sparks. In another study, Laggner et al. reported that H2S is able to inhibit angiotensin-converting enzyme (ACE) activity of endothelial cells and hence is deemed to have a potential for decreasing blood pressure. Suppression of H2S production either pharmacologically or genetically leads to increased blood pressure. Mok et al. found that CSE inhibitors given in hemorrhagic shock led to reduced levels of H2S, increased blood pressure and decreased heart rate. The mechanism of vasodilation remain to be further investigated, the role of H2S as a vasodilator is well accepted and there is increasing interest in employing H2S-releasing agents for hypertension treatment.
Antioxidative effects
Oxidative stress is essentially an imbalance between prooxidant and antioxidant systems. Oxidative stress-induced cellular injury is often caused by excessive formation of reactive oxygen species (ROS) such as peroxynitrite (ONOO-), hydrogen peroxide (H2O2) and superoxide anion (O2-). The release of ROS can cause a number of cellular maladaptations, including lipid peroxidation, protein oxidation to inactive state, and DNA strand breaks. In addition, the majority of heart diseases is associated with ROS generation, including myocardial ischemia-reperfusion (I/R), cardiac hypertrophy, myocardial fibrosis and arrhythmias. H2S has been reported as a strong antioxidant, which provides protective effects in many tissues, including vascular smooth muscle cells, cardiomyocytes and neurons. The robust antioxidant actions of H2S are associated with direct scavenging of ROS and/or increased expressions of antioxidant enzymes. H2S as a direct scavenger can neutralize cytotoxic reactive species and directly destroys organic hydroperoxides of pathobiological importance.
Zhu et al. found that 12-week estrogen treatment increased the levels of catalase and superoxide dismutase (SOD), which is associated with the increase of CSE expression and endogenous H2S generation in the myocardium of ovariectomized rats. Estrogen substitution reduced the pro-inflammatory cytokine levels, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). In another study, Szabó et al. demonstrated that H2S decreased lipid peroxidation by scavenging H2O2 and O2- in a model of isoproterenol-induced myocardial injury. It has been reported that H2S inhibited mitochondrial complex IV activity and increased Mn-SOD and CuZn-SOD, whereas the levels of ROS were decreased in cardiomyocytes during I/R.
Anti-inflammation
Studies have shown that H2S shows anti-inflammatory and pro-inflammatory effects during inflammatory processes. The impact of H2S on inflammatory response is dependent on not only H2S concentration, but also on the rate of H2S production. However, the antioxidant role of H2S plays a dominant role in heart diseases. Elrod et al. reported that the delivery of H2S limited the extent of infarct size and preserved left ventricular function in an in vivo I/R mouse model. H2S-treated animals showed a reduction in myeloperoxidase (MPO) activity and had no significant increase in IL-1β after 4 h reperfusion. Their findings demonstrate that H2S may be of value in cytoprotection during the evolution of myocardial infarction and that either administration of H2S or the modulation of endogenous production may be of clinical benefit in ischemic disorders. Sodha et al. found that sodium hydrosulfide (NaHS), a H2S donor, treatment decreased the levels of TNF-α, IL-6, and IL-8 as well as the activity of MPO. H2S restrained the extent of inflammation and limited the extent of myocardial infarction by preventing leukocyte transmigration and cytokine release.
Angiogenesis
It has been reported that H2S serves as an endogenous stimulator of angiogenic response. Angiogenesis is an important process in chronic ischemia as a poorly vascularized tissue will result in loss of function. The increasing myocardial vascularity and perfusion are critical to prevent the progression of heart failure. Qipshidze et al. found that H2S-treated mice showed an improvement in cardiac function and enhancement of cardiac angiogenesis. Their results suggest that H2S has cytoprotective and angioprotective effects during evolution of MI. In another model, H2S induced angiogenesis in the myocardium and retarded the progression of left ventricle remodeling. In in vitro studies, low concentrations of H2S elevated endothelial cell number, cell migration and capillary morphogenesis. In vitro and in vivo results showed that stimulation of endothelial cells with vascular endothelial growth factor (VEGF) increased H2S release, while pharmacological inhibition of H2S production or KATP channels or silencing of CSE attenuated VEGF signaling and migration of endothelial cells. These results implicate endothelial H2S synthesis in the pro-angiogenic action of VEGF. Aortic rings isolated from CSE knockout mice exhibited markedly reduced microvessel formation in response to VEGF. Givvimani et al. found that H2S induced MMP-2 activation and inhibited MMP-9 activation, thus promoting angiogenesis, and mitigated transition from compensatory cardiac hypertrophy to heart failure in a mouse model. Multiple signaling mechanisms are responsible for H2S-induced angiogenesis, including phosphatidylinositol 3-kinase (PI3K) and Akt activation. H2S can also activate hypoxia inducible factor-1α (HIF-1a)/VEGF pathway. Moreover, the angiogenic pathway may be stimulated through the activation of KATP channels.