Abstract
Background and PurposeCalcification 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 ApproachEffects 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 ResultsIn 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 ImplicationsThe endogenous CSE‐CBS/H2S system exerts anti‐calcification effects in heart valves providing a novel therapeutic approach to prevent hardening of valves.Linked ArticlesThis 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
Highlights
In the developed countries, calcific aortic valve disease (CAVD), an actively regulated disease process, is the most common valvular heart disease with high morbidity and mortality (Yutzey et al, 2014)
Increased phosphate levels are a significant risk factor for CAVD and have been demonstrated in many studies to act as a key regulator of vascular calcification (Adeney et al, 2009; Giachelli, 2009; Hruska, Mathew, Lund, Qiu, & Pratt, 2008)
This induces osteoblastic transition of vascular smooth muscle cells via a process that is accompanied by translocation of runt‐related transcription factor 2 (RUNX2) from the cytosol into the nucleus required for osteoblast differentiation, bone matrix gene expression, and, bone mineralization (Komori, 2006; Zarjou et al, 2009)
Summary
Calcific aortic valve disease (CAVD), an actively regulated disease process, is the most common valvular heart disease with high morbidity and mortality (Yutzey et al, 2014). Our laboratory demonstrated that NaSH (a H2S donor compound) significantly inhibits the mineralization of vascular smooth muscle cells (Zavaczki et al, 2011). Jiang, Wu, Li, Geng, & Tang (2005) and many groups have shown cystathionine γ‐lyase (CSE) in cardiac tissue and it is important for normal heart function (Chen, Xin, & Zhu, 2007) They demonstrated that disturbance of H2S production contributed to the development of heart diseases as manifested by lower levels of H2S in plasma, in patients with coronary heart disease (Jiang et al 2005; Shen, Shen, Luo, Guo, & Zhu, 2015). Anti‐calcification occurs via inhibiting phosphate uptake, preventing nuclear translocation of RUNX2, and increasing pyrophosphate levels. H2S‐releasing donors and CSE/CBS‐derived H2S have therapeutic potential in calcific aortic valve disease. Our study identifies a novel potential treatment for preventing and/or reversing valvular calcification
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