Hydrogen sulfide inhibits aortic valve calcification in heart via regulating RUNX2 by NF-κB, a link between inflammation and mineralization
| Autor: | László Potor, József Balla, Katalin Éva Sikura, Ibolya Fürtös, Zoltán Hendrik, Zsolt Combi, Péter Gergely, György Balla, Matthew Whiteman, Gábor Méhes, Tamás Szerafin, Lívia Beke |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Aortic valve VIC valvular interstitial cells medicine.medical_treatment AP72 4-methoxyphenyl piperidinylphosphinodithioc acid cVIC control healthy valve interstitial cells CBS Cystathionine beta-synthase Pathogenesis 0302 clinical medicine TNF-α tumor necrosis factor α lcsh:R5-920 Multidisciplinary biology AP72 CSE Cystathionine gamma-lyase Chemistry H2S medicine.anatomical_structure Cytokine STED Stimulated Emission Depletion Nanoscopy 030220 oncology & carcinogenesis Knockout mouse mHAV healthy mouse aortic valve Aortic valve calcification medicine.symptom lcsh:Medicine (General) medicine.medical_specialty IL-1β interleukin-1β NF-κB nuclear factor-κB Inflammation Article 03 medical and health sciences Internal medicine medicine AS stenotic aortic valve with calcification lcsh:Science (General) ComputingMethodologies_COMPUTERGRAPHICS CAVD ApoE-/- apolipoprotein E-deficient mice medicine.disease mVIC mouse valvular interstitial cells Cystathionine beta synthase CAVD calcific aortic valve disease Apolipoprotein E knockout mice 030104 developmental biology Endocrinology HAV healthy aortic valve from suicide patients biology.protein Calcification lcsh:Q1-390 |
| Zdroj: | Journal of Advanced Research Journal of Advanced Research, Vol 27, Iss, Pp 165-176 (2021) |
| ISSN: | 2090-1224 2090-1232 |
| Popis: | Graphical abstract Highlights • H2S derived from CSE/CBS inhibits inflammation and calcification of valvular interstitial cells. • H2S releasing molecules inhibits inflammation and calcification of valvular interstitial cells. • H2S inhibits inflammation and calcification in aortic valve of apolipoprotein E deficient mice. • H2S suppresses nuclear translocation of NF-κB and subsequent expression of IL-1β and TNF-α. • Activation of Runx2, its nuclear translocation is mediated by NF-κB in calcifying conditions. • Inflammation and calcification are connected via master transcription factors, NF-κB and Runx2. Introduction 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. Methods and results Expression 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. Conclusions Hydrogen 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. |
| Databáze: | OpenAIRE |
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