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

Abstract

Background and Purpose Calcification of heart valves is a frequent pathological finding in chronic kidney disease and in elderly patients. Hydrogen sulfide (H2S) may exert anti‐calcific actions. Here we investigated H2S as an inhibitor of valvular calcification and to identify its targets in the pathogenesis. Experimental Approach Effects of H2S on osteoblastic transdifferentiation of valvular interstitial cells (VIC) isolated from samples of human aortic valves were studied using immunohistochemistry and western blots. We also assessed H2S on valvular calcification in apolipoprotein E‐deficient (ApoE−/−) mice. Key Results In human VIC, H2S from donor compounds (NaSH, Na2S, GYY4137, AP67, and AP72) inhibited mineralization/osteoblastic transdifferentiation, dose‐dependently in response to phosphate. Accumulation of calcium in the extracellular matrix and expression of osteocalcin and alkaline phosphatase was also inhibited. RUNX2 was not translocated to the nucleus and phosphate uptake was decreased. Pyrophosphate generation was increased via up‐regulating ENPP2 and ANK1. Lowering endogenous production of H2S by concomitant silencing of cystathionine γ‐lyase (CSE) and cystathionine β‐synthase (CBS) favoured VIC calcification. analysis of human specimens revealed higher Expression of CSE in aorta stenosis valves with calcification (AS) was higher than in valves of aortic insufficiency (AI). In contrast, tissue H2S generation was lower in AS valves compared to AI valves. Valvular calcification in ApoE−/− mice on a high‐fat diet was inhibited by H2S. Conclusions and Implications The endogenous CSE‐CBS/H2S system exerts anti‐calcification effects in heart valves providing a novel therapeutic approach to prevent hardening of valves. Linked Articles This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc

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

“…In apolipoprotein E deficient mice kept on high-fat diet valvular calcification appears [3] and that is accompanied by valvular inflammation ( Fig. 1 ) as it was earlier revealed in CAVD [30] .…”

“…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] . Administration of AP72 intraperitoneally significantly inhibited the thickening of the aortic valves and the expression of inflammatory cytokines IL1-β and TNF-α ( Fig.…”

“…We recently observed that mitigation of endogenous H 2 S production by lowering CSE and CBS expression promotes calcification of valvular interstitial cells [3] . Therefore, to test whether the anti-inflammatory effect of endogenously produced H 2 S also exist we performed experiments employing double silencing of CSE and CBS.…”

“…Calcific aortic valve disease (CAVD) is the most common indication for surgical aortic valve replacement in the world [1] . CAVD is particularly dominant in national populations over age 65 (2–7%) [2] and also a frequent disorder in chronic kidney disease (CKD) [3] . The percentage of CAVD has been increasing in the last 10 years and the incidence of the disease expected to increase in the future [4] , [5] , [6] , [7] .…”

Role of Interleukin 17A in Aortic Valve Inflammation in Apolipoprotein E-deficient Mice

“…Similarly, significant calcium deposits in aortic valve of HFD-treated ApoE -/mice by alizarin red staining [7] . Currently, ApoE -/mice fed with HFD are the common animal models for aortic valve inflammation study [7][8][9] .…”