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Cardiovascular phenotype of mice lacking 3-mercaptopyruvate sulfurtransferase.
Biochem Pharmacol. 2020 06; 176:113833.BP

Abstract

RATIONALE

Hydrogen sulfide (H2S) is a physiological mediator that regulates cardiovascular homeostasis. Three major enzymes contribute to the generation of endogenously produced H2S, namely cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). Although the biological roles of CSE and CBS have been extensively investigated in the cardiovascular system, very little is known about that of 3-MST. In the present study we determined the importance of 3-MST in the heart and blood vessels, using a genetic model with a global 3-MST deletion.

RESULTS

3-MST is the most abundant transcript in the mouse heart, compared to CSE and CBS. 3-MST was mainly localized in smooth muscle cells and cardiomyocytes, where it was present in both the mitochondria and the cytosol. Levels of serum and cardiac H2S species were not altered in adult young (2-3 months old) 3-MST-/- mice compared to WT animals. No significant changes in the expression of CSE and CBS were observed. Additionally, 3-MST-/- mice had normal left ventricular structure and function, blood pressure and vascular reactivity. Interestingly, genetic ablation of 3-MST protected mice against myocardial ischemia reperfusion injury, and abolished the protection offered by ischemic pre- and post-conditioning. 3-MST-/- mice showed lower expression levels of thiosulfate sulfurtransferase, lower levels of cellular antioxidants and elevated basal levels of cardiac reactive oxygen species. In parallel, 3-MST-/- mice showed no significant alterations in endothelial NO synthase or downstream targets. Finally, in a separate cohort of older 3-MST-/- mice (18 months old), a hypertensive phenotype associated with cardiac hypertrophy and NO insufficiency was observed.

CONCLUSIONS

Overall, genetic ablation of 3-MST impacts on the mouse cardiovascular system in an age-dependent manner. Loss of 3-MST exerts a cardioprotective role in young adult mice, while with aging it predisposes them to hypertension and cardiac hypertrophy.

Authors+Show Affiliations

Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece; Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece.Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, German Centre for Cardiovascular Research (DZHK) Partner Site Rhein-Main, Frankfurt am Main, Germany.Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA."George P. Livanos and Marianthi Simou" Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece.Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece.Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, German Centre for Cardiovascular Research (DZHK) Partner Site Rhein-Main, Frankfurt am Main, Germany.Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy.Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy.Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece.Isotope Research Center, Nippon Medical School, Tokyo, Japan.Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy.Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, German Centre for Cardiovascular Research (DZHK) Partner Site Rhein-Main, Frankfurt am Main, Germany.Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA.Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece; Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece. Electronic address: apapapet@pharm.uoa.gr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32027885

Citation

Peleli, Maria, et al. "Cardiovascular Phenotype of Mice Lacking 3-mercaptopyruvate Sulfurtransferase." Biochemical Pharmacology, vol. 176, 2020, p. 113833.
Peleli M, Bibli SI, Li Z, et al. Cardiovascular phenotype of mice lacking 3-mercaptopyruvate sulfurtransferase. Biochem Pharmacol. 2020;176:113833.
Peleli, M., Bibli, S. I., Li, Z., Chatzianastasiou, A., Varela, A., Katsouda, A., Zukunft, S., Bucci, M., Vellecco, V., Davos, C. H., Nagahara, N., Cirino, G., Fleming, I., Lefer, D. J., & Papapetropoulos, A. (2020). Cardiovascular phenotype of mice lacking 3-mercaptopyruvate sulfurtransferase. Biochemical Pharmacology, 176, 113833. https://doi.org/10.1016/j.bcp.2020.113833
Peleli M, et al. Cardiovascular Phenotype of Mice Lacking 3-mercaptopyruvate Sulfurtransferase. Biochem Pharmacol. 2020;176:113833. PubMed PMID: 32027885.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cardiovascular phenotype of mice lacking 3-mercaptopyruvate sulfurtransferase. AU - Peleli,Maria, AU - Bibli,Sofia-Iris, AU - Li,Zhen, AU - Chatzianastasiou,Athanasia, AU - Varela,Aimilia, AU - Katsouda,Antonia, AU - Zukunft,Sven, AU - Bucci,Mariarosaria, AU - Vellecco,Valentina, AU - Davos,Constantinos H, AU - Nagahara,Noriyuki, AU - Cirino,Giuseppe, AU - Fleming,Ingrid, AU - Lefer,David J, AU - Papapetropoulos,Andreas, Y1 - 2020/02/04/ PY - 2019/11/18/received PY - 2020/01/30/accepted PY - 2020/2/7/pubmed PY - 2020/10/27/medline PY - 2020/2/7/entrez KW - 3-mercaptopyruvate transferase (3-MST) KW - Aging KW - Blood pressure KW - Myocardial infarction KW - Nitric Oxide (NO) KW - Reactive Oxygen Species (ROS) SP - 113833 EP - 113833 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 176 N2 - RATIONALE: Hydrogen sulfide (H2S) is a physiological mediator that regulates cardiovascular homeostasis. Three major enzymes contribute to the generation of endogenously produced H2S, namely cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). Although the biological roles of CSE and CBS have been extensively investigated in the cardiovascular system, very little is known about that of 3-MST. In the present study we determined the importance of 3-MST in the heart and blood vessels, using a genetic model with a global 3-MST deletion. RESULTS: 3-MST is the most abundant transcript in the mouse heart, compared to CSE and CBS. 3-MST was mainly localized in smooth muscle cells and cardiomyocytes, where it was present in both the mitochondria and the cytosol. Levels of serum and cardiac H2S species were not altered in adult young (2-3 months old) 3-MST-/- mice compared to WT animals. No significant changes in the expression of CSE and CBS were observed. Additionally, 3-MST-/- mice had normal left ventricular structure and function, blood pressure and vascular reactivity. Interestingly, genetic ablation of 3-MST protected mice against myocardial ischemia reperfusion injury, and abolished the protection offered by ischemic pre- and post-conditioning. 3-MST-/- mice showed lower expression levels of thiosulfate sulfurtransferase, lower levels of cellular antioxidants and elevated basal levels of cardiac reactive oxygen species. In parallel, 3-MST-/- mice showed no significant alterations in endothelial NO synthase or downstream targets. Finally, in a separate cohort of older 3-MST-/- mice (18 months old), a hypertensive phenotype associated with cardiac hypertrophy and NO insufficiency was observed. CONCLUSIONS: Overall, genetic ablation of 3-MST impacts on the mouse cardiovascular system in an age-dependent manner. Loss of 3-MST exerts a cardioprotective role in young adult mice, while with aging it predisposes them to hypertension and cardiac hypertrophy. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/32027885/Cardiovascular_phenotype_of_mice_lacking_3_mercaptopyruvate_sulfurtransferase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(20)30043-5 DB - PRIME DP - Unbound Medicine ER -