Hydrogen sulfide as an anti-calcification stratagem in human aortic valve: Altered biogenesis and mitochondrial metabolism of H2S lead to H2S deficiency in calcific aortic valve disease

Hydrogen sulfide (H2S) was previously revealed to inhibit osteoblastic differentiation of valvular interstitial cells (VICs), a pathological feature in calcific aortic valve disease (CAVD). This study aimed to explore the metabolic control of H2S levels in human aortic valves.Lower levels of bioavailable H2S and higher levels of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) were detected in aortic valves of CAVD patients compared to healthy individuals, accompanied by higher expression of cystathionine gamma-lyase (CSE) and same expression of cystathionine beta-synthase (CBS). Increased biogenesis of H2S by CSE was found in the aortic valves of CAVD patients which is supported by increased production of lanthionine. In accordance, healthy human aortic VICs mimic human pathology under calcifying conditions, as elevated CSE expression is associated with low levels of H2S. The expression of mitochondrial enzymes involved in H2S catabolism including sulfide quinone oxidoreductase (SQR), the key enzyme in mito-chondrial H2S oxidation, persulfide dioxygenase (ETHE1), sulfite oxidase (SO) and thiosulfate sulfurtransferase (TST) were up-regulated in calcific aortic valve tissues, and a similar expression pattern was observed in response to high phosphate levels in VICs. AP39, a mitochondria-targeting H2S donor, rescued VICs from an osteoblastic phenotype switch and reduced the expression of IL-1 beta and TNF-alpha in VICs. Both pro-inflammatory cytokines aggravated calcification and osteoblastic differentiation of VICs derived from the calcific aortic valves. In contrast, IL-1 beta and TNF-alpha provided an early and transient inhibition of VICs calcification and osteoblastic dif-ferentiation in healthy cells and that effect was lost as H2S levels decreased. The benefit was mediated via CSE induction and H2S generation.

Automated summary

This study aimed to explore the metabolic control of H2S levels in human aortic valves. The results showed that lower levels of bioavailable H2S and higher levels of pro-inflammatory cytokines were detected in aortic valves of patients with calcific aortic valve disease. Increased biogenesis and decreased degradation of H2S were observed in calcific aortic valve tissues. Mitochondria-targeting H2S donor could rescue the osteoblastic phenotype switch and reduce the expression of pro-inflammatory cytokines.