Activation of sirtuin 1/3 improves vascular hyporeactivity in severe hemorrhagic shock by alleviation of mitochondrial damage

Pengyun Li; Xianzhong Meng; Huining Bian; Nana Burns; Ke-seng Zhao; Rui Song

doi:10.18632/oncotarget.6076

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Research Papers: Pathology:

Activation of sirtuin 1/3 improves vascular hyporeactivity in severe hemorrhagic shock by alleviation of mitochondrial damage

Pengyun Li, Xianzhong Meng, Huining Bian, Nana Burns, Ke-seng Zhao and Rui Song _

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Oncotarget. 2015; 6:36998-37011. https://doi.org/10.18632/oncotarget.6076

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Abstract

Pengyun Li1,2, Xianzhong Meng3, Huining Bian4, Nana Burns5, Ke-seng Zhao1 and Rui Song1

1 Guangdong Key Laboratory of Shock and Microcirculation Research, Department of Pathophysiology, Southern Medical University, Guangzhou, China

2 Key Laboratory of Medical Electrophysiology, and Institute of Cardiovascular Research, Sichuan Medical University, Luzhou, China

3 Department of Surgery, University of Colorado Denver, Aurora, CO, USA

4 Department of Burns, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

5 Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA

Correspondence to:

Rui Song, email:

Ke-seng Zhao, email:

Keywords: vasoreactivity, sirtuin, deacetylation, mitochondria, hemorrhagic shock, Pathology Section

Received: July 11, 2015 Accepted: September 24, 2015 Published: October 12, 2015

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.

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Research Papers: Pathology:

Activation of sirtuin 1/3 improves vascular hyporeactivity in severe hemorrhagic shock by alleviation of mitochondrial damage

Abstract