title: Activation of sirtuin 1/3 improves vascular hyporeactivity in severe hemorrhagic shock by alleviation of mitochondrial damage.
abstract: Vascular hyporeactivity is one of the major causes responsible for refractory hypotension and associated mortality in severe hemorrhagic shock. Mitochondrial permeability transition (mPT) pore opening in arteriolar smooth muscle cells (ASMCs) is involved in the pathogenesis of vascular hyporeactivity. However, the molecular mechanism underlying mitochondrial injury in ASMCs during hemorrhagic shock is not well understood. Here we produced an in vivo model of severe hemorrhagic shock in adult Wistar rats. We found that sirtuin (SIRT)1/3 protein levels and deacetylase activities were decreased in ASMCs following severe shock. Immunofluorescence staining confirmed reduced levels of SIRT1 in the nucleus and SIRT3 in the mitochondria, respectively. Acetylation of cyclophilin D (CyPD), a component of mPT pore, was increased. SIRT1 activators suppressed mPT pore opening and ameliorated mitochondrial injury in ASMCs after severe shock. Furthermore, administration of SIRT1 activators improved vasoreactivity in rats under severe shock. Our data suggest that epigenetic mechanisms, namely histone post-translational modifications, are involved in regulation of mPT by SIRT1/SIRT3- mediated deacetylation of CyPD. SIRT1/3 is a promising therapeutic target for the treatment of severe hemorrhagic shock.
authors.affiliation: Guangdong Key Laboratory of Shock and Microcirculation Research, Department of Pathophysiology, Southern Medical University, Guangzhou, China.|Key Laboratory of Medical Electrophysiology, and Institute of Cardiovascular Research, Sichuan Medical University, Luzhou, China.
authors.forename: Pengyun
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Burns, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Huining
authors.initials: H
authors.lastname: Bian
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Nana
authors.initials: N
authors.lastname: Burns
authors.affiliation: Guangdong Key Laboratory of Shock and Microcirculation Research, Department of Pathophysiology, Southern Medical University, Guangzhou, China.
authors.forename: Ke-seng
authors.initials: KS
authors.lastname: Zhao
authors.affiliation: Guangdong Key Laboratory of Shock and Microcirculation Research, Department of Pathophysiology, Southern Medical University, Guangzhou, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
mesh_terms: D000818:Animals; D001160:Arterioles / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D056564:Sirtuin 1 / Q000378:metabolism*; D056565:Sirtuin 2 / Q000378:metabolism*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C097475:Sirt2 protein, rat; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D056565:Sirtuin 2
keywords: Pathology Section; deacetylation; hemorrhagic shock; mitochondria; sirtuin; vasoreactivity