Roles of H2S in cardiovascular diseases

Myocardial I/R injury and myocardial infarction

During ischemia, the lack of blood flow to the heart causes an imbalance between oxygen demand and supply and results in damage and dysfunction of the cardiac tissue. Although reperfusion relieves ischemia, it also results in a complex reaction that leads to cell injury caused by inflammation and oxidative damage. Growing evidence indicates that H₂S is involved in myocardial infarction and I/R injury. H₂S protects cardiac muscle from I/R injury by increasing the production of NO. H₂S is known to interact with the other biological mediators and signal transduction components to produce its effects in the vascular system. H₂S can activate eNOS and can augment NO bioavailability, highlighting that there is an interaction between NO and H₂S during physiological processes. In CSE gene knockout mice, the levels of H₂S as well as the levels of NO metabolites were decreased, whereas administration of H₂S rescued the heart from I/R injury by eNOS activation.

Osipov et al. demonstrated that infusion of H₂S reduced myocardial necrosis after IR injury, even though some markers of apoptosis and autophagy were affected in both H₂S-treated groups. Thus, their current results indicated that infusion of H₂S throughout IR may offer better myocardial protection from IR injury. H₂S postconditioning also effectively protected isolated I/R rat hearts through activation of Janus kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) signaling pathway. Elrod et al. reported that that modulation of endogenously produced H₂S by cardiac-specific overexpression of CSE significantly limited the extent of injury and improved cardiac function after 45 min of ischemia and 72 hours of reperfusion.

Atherosclerosis

The atherosclerotic process is characterized, in its earliest stages, by perturbations in endothelial function. The development of atherosclerosis and atherogenesis is a multifactorial and complex process with involvement of vascular inflammation, VSMC proliferation, thrombus formation, infiltration of monocytes and their differentiation into macrophages, and its transformation into foam cells. Mani et al. demonstrated that six-week-old CSE gene knockout (KO) mice fed with atherogenic diet developed early fatty streak lesions in the aortic root, increased oxidative stress in lesions and enhanced aortic intimal proliferation. Treatment of CSE-KO mice with NaHS significantly inhibited the progression of atherosclerosis. The CSE/H₂S pathway is an important therapeutic target for protection against atherosclerosis. A critical step in the development of the atherosclerotic plaque is the transformation of macrophages into foam cells. This involves the uptake of oxidized LDL (oxLDL) by macrophages. H₂S could mediate the atherogenic cascade by decreasing oxidative modification of oxLDL and dyslipidemia; decreasing smooth muscle cell proliferation, calcification and migration and decreasing ROS level. Chen et al. reported that serum H₂S concentration shows a negative correlation with arterial pathological damage scores in atherosclerotic rat model, and administration of exogenous H₂S reduces atherosclerotic lesions by improving the damage of vessels and inhibiting the expression of VEGF.

Hypertension

It has been reported that the decrease in CSE/H₂S activity contributes to maternal hypertension. Yang et al. found that CSE-deficient mice developed severe endothelial dysfunction and hypertension within 8 weeks of birth. H₂S replacement reduced systolic blood pressure in both CSE^-/- and CSE ^+/- mice, suggesting that the H₂S pathway confers a protection against hypertension. H₂S seems to be a physiologic vasodilator and regulator of blood pressure. Ahmad et al. reported that administration of exogenous H₂S reduced blood pressure and prevented the progression of diabetic nephropathy in spontaneously hypertensive rats.

Cardiac hypertrophy

Pathological hypertrophy occurs in response to chronically increased pressure overload or volume overload, or following myocardial infarction. It has been confirmed that H₂S plays a protecting role against cardiac hypertrophy. Lu et al. found that H₂S improved cardiac function and reduced myocardial apoptosis in isoproterenol-induced hypertrophy rat model. They concluded that H₂S reduced oxidative stress due to cardiac hypertrophy through the cardiac mitochondrial pathway. In another endothelium-induced cardiac hypertrophy rat model, Yang et al. reported that H₂S treatment decreased left ventricular mass index, volume fraction of cardiac interstitial collagen and myocardial collagen content and improved cardiac hypertrophy.

Cardiac arrhythmias

The primary causes of I/R-induced arrhythmias are considered to be the endogenous metabolites, such as ROS, thrombin, and platelet activating factor produced and accumulated in the myocardium during reperfusion. Zhang et al. found that reperfusion with NaHS after ischemia reduced the development of arrhythmias in the isolated Langendorff-perfused rat heart and improved cardiac function during I/R. These effects depend on the opening of K_ATP channel. It has been documented that H₂S replacement therapy may be a significant cardioprotective and antiarrhythmic intervention for those people with chronic ischemic heart disease whose plasma H₂S level is reduced. 

Role of Hydrogen Sulfide in the Carotid Body in Heart Failure

H₂S is an important signaling molecule in the cardiovascular and nervous systems. It has been shown that H2S controls vascular relaxation and prevents apoptosis. H₂S synthesis has been attributed to three enzymes, cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfur transferase with CSE and CBS as the major sources for endogenous H2S levels. Recent evidence indicates that H₂S can also participate as a messenger in the carotid body chemoreceptor function. It is found also that CSE is constitutively expressed in the carotid body glomus cells and that hypoxic stimulation of the carotid body in vitro induced H₂S formation. Moreover, transgenic CSE−/− mice display impaired carotid body chemosensory responses to acute hypoxia.

H₂S has been reported to be cardioprotective in myocardial ischemia due to its ability to preserve mitochondrial function and prevent cardiomyocyte apoptosis. Several treatments targeting the H₂S pathway prevent the progression of the cardiovascular dysfunction associated with heart failure. Indeed, pharmacotherapies designed to increase H₂S levels have been proposed as a novel treatment to reduce the impact of heart failure on cardiac function. Mice with cardiac-selective overexpression of CSE present low levels of cardiomyocyte apoptosis following ischemia-reperfusion heart insult. Moreover, treatment with NaHS, an H₂S donor, protects the heart from oxidative stress and mitochondrial dysfunction associated with volume overload heart failure. Thus, evidence indicates that H₂S is cytoprotective in the failing heart. Recent studies by Prabhakar suggest that H₂S function in the carotid body may be linked to HO-2 due to an inhibitory influence of CO on CSE enzyme activity. Some findings suggested that CO physiologically inhibits the CSE-dependent generation of H₂S and that hypoxia, which reduces HO-2 activity and CO levels, reverses the CO-mediated CSE inhibition to augment H₂S formation and chemoreceptor stimulation, and this intriguing concept may be functionally relevant to the heart failure state. Downregulation of HO-2 in the carotid body in heart failure would promote CSE activity and H₂S-mediated modulation of carotid body chemoreceptor afferent activity as observed in heart failure rats.