Maria Peleli1, Sofia-Iris Bibli2, Zhen Li3, Athanasia Chatzianastasiou4, Aimilia Varela5, Antonia Katsouda5, Sven Zukunft2, Mariarosaria Bucci6, Valentina Vellecco6, Constantinos H Davos5, Noriyuki Nagahara7, Giuseppe Cirino6, Ingrid Fleming2, David J Lefer3, Andreas Papapetropoulos8. 1. 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. 2. 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. 3. Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA. 4. "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. 5. Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece. 6. Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy. 7. Isotope Research Center, Nippon Medical School, Tokyo, Japan. 8. 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.
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.
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.
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