Abstract
IntroductionHydrogen sulfide (H2S) was revealed to inhibit aortic valve calcification and inflammation was implicated in the pathogenesis of calcific aortic valve disease (CAVD). ObjectivesWe investigate whether H2S inhibits mineralization via abolishing inflammation. Methods and resultsExpression of pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) were increased in patients with CAVD and in calcified aortic valve of ApoE-/- mice. Administration of H22S releasing donor (4-methoxyphenyl piperidinylphosphinodithioc acid (AP72)) exhibited inhibition on both calcification and inflammation in aortic valve of apolipoprotein E knockout mice (ApoE-/-) mice is reflected by lowering IL-1β and TNF-α levels. Accordingly, AP72 prevented the accumulation of extracellular calcium deposition and decreased nuclear translocation of nuclear factor-κB (NF-κB) in human valvular interstitial cells (VIC). This was also accompanied by reduced cytokine response. Double-silencing of endogenous H2S producing enzymes, Cystathionine gamma-lyase (CSE) and Cystathionine beta-synthase (CBS) in VIC exerted enhanced mineralization and higher levels of IL-1β and TNF-α. Importantly, silencing NF-κB gene or its pharmacological inhibition prevented nuclear translocation of runt-related transcription factor 2 (Runx2) and subsequently the calcification of human VIC. Increased levels of NF-κB and Runx2 and their nuclear accumulation occurred in ApoE-/- mice with a high-fat diet. Administration of AP72 decreased the expression of NF-κB and prevented its nuclear translocation in VIC of ApoE-/- mice on a high-fat diet, and that was accompanied by a lowered pro-inflammatory cytokine level. Similarly, activation of Runx2 did not occur in VIC of ApoE-/- mice treated with H2S donor. Employing Stimulated Emission Depletion (STED) nanoscopy, a strong colocalization of NF-κB and Runx2 was detected during the progression of valvular calcification. ConclusionsHydrogen sulfide inhibits inflammation and calcification of aortic valve. Our study suggests that the regulation of Runx2 by hydrogen sulfide (CSE/CBS) occurs via NF-κB establishing a link between inflammation and mineralization in vascular calcification.
Highlights
Hydrogen sulfide (H2S) was revealed to inhibit aortic valve calcification and inflammation was implicated in the pathogenesis of calcific aortic valve disease (CAVD)
We found that using interfering RNAs for Cystathionine gamma-lyase (CSE)/Cystathionine beta-synthase (CBS) significantly enhanced the expression of both IL1-b and tumor necrosis factor a (TNF-a) in human vascular interstitial cells (Fig. 3A and B) exposed to high phosphate suggesting that H2S controls the progress of inflammation under calcifying conditions
It is well established that nuclear factor-jB (NF-jB) regulates pro-inflammatory signaling pathway and its activation is based on its nuclear translocation followed by pro-inflammatory cytokine expressions such as interleukin 1b (IL-1b) and tumor necrosis factor a (TNF-a) [19]
Summary
Hydrogen sulfide (H2S) was revealed to inhibit aortic valve calcification and inflammation was implicated in the pathogenesis of calcific aortic valve disease (CAVD). Objectives: We investigate whether H2S inhibits mineralization via abolishing inflammation. Peer review under responsibility of Cairo University. Calcific aortic valve disease (CAVD) is the most common indication for surgical aortic valve replacement in the world [1]. In calcific aortic valve disease, the valvular interstitial cells transdifferentiate into osteoblast-like cells contributing to the mineralization of tissue [1,9]. Nuclear translocation of osteogenic transcription factor Runx initiates the transition of cells towards an osteoblast phenotype in response to various pathological stimuli such as high phosphate [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
