Hydrogen Sulfide Abrogates Hemoglobin‐Lipid Interaction in Atherosclerotic Lesion

Abstract

The infiltration of red blood cells into atheromatous plaques is implicated in atherogenesis. Inside the lesion, hemoglobin (Hb) is oxidized to ferri- and ferrylHb which exhibit prooxidant and proinflammatory activities. Cystathione gamma-lyase- (CSE-) derived H2S has been suggested to possess various antiatherogenic actions. Expression of CSE was upregulated predominantly in macrophages, foam cells, and myofibroblasts of human atherosclerotic lesions derived from carotid artery specimens of patients. A similar pattern was observed in aortic lesions of apolipoprotein E-deficient mice on high-fat diet. We identified several triggers for inducing CSE expression in macrophages and vascular smooth muscle cells including heme, ferrylHb, plaque lipids, oxidized low-density lipoprotein, tumor necrosis factor-α, and interleukin-1β. In the interplay between hemoglobin and atheroma lipids, H2S significantly mitigated oxidation of Hb preventing the formation of ferrylHb derivatives, therefore providing a novel function as a heme-redox-intermediate-scavenging antioxidant. By inhibiting Hb-lipid interactions, sulfide lowered oxidized Hb-mediated induction of adhesion molecules in endothelium and disruption of endothelial integrity. Exogenous H2S inhibited heme and Hb-mediated lipid oxidation of human atheroma-derived lipid and human complicated lesion. Our study suggests that the CSE/H2S system represents an atheroprotective pathway for removing or limiting the formation of oxidized Hb and lipid derivatives in the atherosclerotic plaque.

Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease

“…Data shown are means ± SEM of five independent experiments. *P < .05, significantly different as indicated; ns, not significant accumulation without calcification (Potor et al, 2018). In the present study, we found that CSE expression was higher in human AS valves known to be associated with calcification, compared with that in AI valves lacking calcification (Figure 5a).…”

“…Human aortic valve leaflets were obtained from patients undergoing valve replacement for stenosis with calcification (AS; N = 52) and patients who had severe insufficiency without calcification (AI; N = 28). The specimens were collected from January 2015 to December 2017 (80 patients; intraperitoneally with AP72 (266-μmol·kg −1 ; N = 5) or vehicle (saline; N = 9) on every other day as previously described (Potor et al, 2018). Aortas were collected after 8 weeks of treatment.…”

Hydrogen sulfide inhibits aortic valve calcification in heart via regulating RUNX2 by NF-κB, a link between inflammation and mineralization

“…Since we previously demonstrated that H 2 S inhibits aortic valve calcification in apolipoprotein E deficient mice (ApoE -/- mice) kept on a high-fat diet [3] , [27] we tested whether it also affects inflammation of aortic valves of ApoE -/- mice kept on a high-fat diet. We utilized AP72, a slow-releasing H 2 S donor, previously found to be a potent inhibitor of valvular mineralization, in our experiments [3] .…”

Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology

“…Indeed, in those lesions, oxidized forms of Hb with the heme in the ferric and ferryl state accumulate and mediate toxicity by promoting radical reactions leading to formation of cross-linked Hb species and lipid modification. Under these circumstances, H 2 S was recently reported to exert protective effects, acting as a reductant of ferryl Hb [ 116 ].…”