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.
Highlights
Severe or irreversible hemorrhagic shock is a lifethreatening situation associated with significant morbidity and mortality directly due to massive blood loss or occurs indirectly to secondary multiple organ failure
Mitochondrial injury and Mitochondrial permeability transition (mPT) pore opening in arteriolar smooth muscle cells (ASMCs) are associated with down-regulation of both sirtuin 1 (SIRT1) and SIRT3 during severe hemorrhagic shock
To determine the changes in mitochondrial phenotype and function during severe hemorrhagic shock, we examined mitochondrial ultrastructural morphology and ATP production in ASMCs isolated from rats with severe hemorrhagic shock
Summary
Severe or irreversible hemorrhagic shock is a lifethreatening situation associated with significant morbidity and mortality directly due to massive blood loss or occurs indirectly to secondary multiple organ failure. Previous studies have shown that ATP depletion in severe shock results from insufficient delivery of nutrients and oxygen, and from cytopathic hypoxia involving damage to and dysfunction of mitochondria in arteriolar smooth muscle cells (ASMCs) [2, 3]. The cellular and molecular mechanisms of mitochondria-derived cytopathic hypoxia underlying the progression of refractory hypotension during severe shock remain elusive. Histone deacetylase sirtuin 1 (SIRT1) emerged as a crucial regulator of mitochondrial biogenesis and function [7, 8]. Resveratrol (Res), a SIRT1 activator, has been shown to restore SIRT1 activity and mitochondrial complex function in the liver, kidney and heart during injury or stress [12,13,14]
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