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
Zsolt Combi,
László Potor,
Péter Nagy,
Katalin Éva Sikura,
Tamás Ditrói,
Eszter Petra Jurányi,
Klaudia Galambos,
Tamás Szerafin,
Péter Gergely,
Matthew Whiteman,
Roberta Torregrossa,
Yuchao Ding,
Lívia Beke,
Zoltán Hendrik,
Gábor Méhes,
György Balla,
József Balla
Affiliations
Zsolt Combi
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary; ELKH-UD Vascular Pathophysiology Research Group, University of Debrecen, 11003, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary
László Potor
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary; ELKH-UD Vascular Pathophysiology Research Group, University of Debrecen, 11003, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary
Péter Nagy
Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary; Institute of Chemistry, Faculty of Science and Technology, University of Debrecen, Debrecen, Hungary; Department of Anatomy and Histology, ELKH Laboratory of Redox Biology, University of Veterinary Medicine, Budapest, Hungary
Katalin Éva Sikura
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary; ELKH-UD Vascular Pathophysiology Research Group, University of Debrecen, 11003, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary
Tamás Ditrói
Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary
Eszter Petra Jurányi
Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary; Doctoral School of Molecular Medicine, Semmelweis University, Budapest, Hungary
Klaudia Galambos
Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary; Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary
Tamás Szerafin
Department of Cardiac Surgery, Faculty of Medicine, University of Debrecen, Hungary
Péter Gergely
Institute of Forensic Medicine, Faculty of Medicine, University of Debrecen, Hungary
Matthew Whiteman
University of Exeter Medical School, St. Luke's Campus, Magdalen Road, Exeter, EX1 2LU, UK
Roberta Torregrossa
University of Exeter Medical School, St. Luke's Campus, Magdalen Road, Exeter, EX1 2LU, UK
Yuchao Ding
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary
Lívia Beke
Institute of Pathology, Faculty of Medicine, University of Debrecen, Hungary
Zoltán Hendrik
Institute of Forensic Medicine, Faculty of Medicine, University of Debrecen, Hungary
Gábor Méhes
Institute of Pathology, Faculty of Medicine, University of Debrecen, Hungary
György Balla
ELKH-UD Vascular Pathophysiology Research Group, University of Debrecen, 11003, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary; Department of Pediatrics, Faculty of Medicine, University of Debrecen, Hungary
József Balla
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary; ELKH-UD Vascular Pathophysiology Research Group, University of Debrecen, 11003, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary; Corresponding author. Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4012, Debrecen, Nagyerdei blvd. 98, Hungary.
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-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were detected in aortic valves of CAVD patients compared to healthy individuals, accompanied by higher expression of cystathionine γ-lyase (CSE) and same expression of cystathionine β-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 mitochondrial 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-1β and TNF-α in VICs. Both pro-inflammatory cytokines aggravated calcification and osteoblastic differentiation of VICs derived from the calcific aortic valves. In contrast, IL-1β and TNF-α provided an early and transient inhibition of VICs calcification and osteoblastic differentiation in healthy cells and that effect was lost as H2S levels decreased. The benefit was mediated via CSE induction and H2S generation.We conclude that decreased levels of bioavailable H2S in human calcific aortic valves result from an increased H2S metabolism that facilitates the development of CAVD. CSE/H2S represent a pathway that reverses the action of calcifying stimuli.
