Hydrogen Sulfide Therapy in Diabetes-Accelerated Atherosclerosis: A Whiff of Success.

Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in diabetes (1). Atherosclerosis occurs earlier and with greater severity in the population with diabetes, leading to a much higher risk of myocardial infarction, stroke, and limb ischemia and amputation. Although numerous factors contribute to the etiology of atherosclerosis, oxidative stress and inflammation play a fundamental role and both processes are exacerbated in diabetes. Given the rapidly growing worldwide incidence of diabetes, there is a critical need for new therapies that target atherogenesis and its clinical manifestations in patients with diabetes. The gasotransmitters nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) have emerged as crucial regulators of vascular disease in diabetes (2). Although NO and CO have been extensively studied, less is known regarding the role of H2S in diabetes. H2S is a colorless, water-soluble gas with the characteristic smell of rotten eggs. It is generated by the metabolism of cysteine by the enzymes cystathionine b-synthase and cystathionine g-lyase or by the concerted action of cysteine amino transferase and 3-mercaptopyruvate sulfurtransferase (Fig. 1). H2S is also produced nonenzymatically from glucose, glutathione, thiosulfate, and sulfur-containing proteins and by the bacterial reduction of sulfur in the intestinal tract (3,4). Although long considered a toxic gas, studies in the past decade have revealed important physiological roles for H2S. H2S promotes blood flow by dilating blood vessels and inhibiting platelet aggregation (3,5). It also exerts potent antioxidant, antiapoptotic, antiinflammatory, and angiogenic responses. H2S elicits many of its biological effects by targeting proteins for S-sulfhydration, where sulfur is added to the thiol groups of reactive cysteine residues resulting in the formation of hydropersulfide (6). More recently, H2S has been shown to mitigate endothelial dysfunction, retinopathy, cardiomyopathy, and nephropathy in experimental animal models of diabetes (7–10), highlighting the protective nature of this molecule. In this issue, Xie et al. (11) further address the role of H2S in diabetes and demonstrate for the first time that this gas suppresses diabetes-accelerated atherosclerosis. They show that daily systemic administration of the slow-releasing H2S donor GYY4137 decreases atherosclerotic lesion size in atheroprone, streptozotocin-induced diabetic mice fed a high-fat diet, independent of any change in circulating blood glucose or cholesterol. The antiatherosclerotic effect of GYY4137 is associated with reductions in macrophage content within the plaque and decreases in the production of superoxide and expression of the adhesion receptors intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the aortic endothelium. Comparable effects are also observed when peritoneal macrophages or endothelial cells are exposed to high concentrations of glucose and oxidized LDL that mimics the in vivo environment encountered in diabetes. However, the protective actions of GYY4137 are lost if GYY4137 is depleted of H2S or if a structural analog of GYY4137 that lacks sulfur is used, indicating that H2S mediates the actions of GYY4137. The authors also demonstrate that GYY4137 activates the transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) via the specific S-sulfhydration of cysteine 151 (Cys151) in Kelch-like ECH-associated protein 1 (Keap1), a repressor protein that binds Nrf2 and promotes its degradation by the ubiquitin proteasome pathway (12). Significantly, deletion or silencing of Nrf2 abolishes the antiatherogenic action of GYY4137 in diabetic mice and cells, illustrating the essential role of Nrf2. In addition, GYY4137 stimulates the expression of heme oxygenase 1 (HO-1) in an Nrf2-dependent manner, and depletion or inhibition of HO-1 abolishes the cellular actions of GYY4137, implicating HO-1 in the antiatherogenic effects of H2S.