The effects of the overexpression of recombinant uncoupling protein 2 on proliferation, migration and plasminogen activator inhibitor 1 expression in human vascular smooth muscle cells

Abstract

Aims/hypothesis: Increased oxidative stress in vascular smooth muscle cells (VSMCs) has been implicated in the pathogenesis of accelerated atherosclerosis in patients with diabetes mellitus. Uncoupling protein 2 (UCP-2) is an important regulator of intracellular reactive oxygen species (ROS) production. We hypothesised that UCP-2 functions as an inhibitor of the atherosclerotic process in VSMCs. Methods: Overexpression of human UCP-2 was performed in primary cultured human VSMCs (HVSMCs) via adenovirus- mediated gene transfer. Its effects on ROS production, AP-1 activity, plasminogen activator inhibitor 1 (PAI-1) gene expression, and cellular proliferation and migration were measured in response to high glucose and angiotensin II (Ang II) concentrations, two major factors in the pathogenesis of atherosclerosis in patients with diabetes and hypertension. Mitochondrial membrane potential and NAD(P)H oxidase activity were also measured. Results: High glucose and Ang II caused transient mitochondrial membrane hyperpolarisation. They also significantly stimulated ROS production, NAD(P)H oxidase activity, mitochondrial membrane potential, AP-1 activity, PAI-1 mRNA expression, and proliferation and migration of HVSMCs. Adenovirus-mediated transfer of the UCP-2 gene reversed all of these effects. Conclusions/interpretation: The present study demonstrates that UCP-2 can modify atherosclerotic processes in HVSMCs in response to high glucose and Ang II. Our data suggest that agents increasing UCP-2 expression in vascular cells may help prevent the development and progression of atherosclerosis in patients with diabetes and hypertension. Keywords Angiotensin II . Atherosclerosis . High glucose . Migration . Plasminogen activator inhibitor 1 . Proliferation . Reactive oxygen species . Uncoupling protein 2 . Vascular smooth muscle cells Abbreviations Ang II: angiotensin II . AP-1: activator protein 1 . HVSMCs: human vascular smooth muscle cells . ODN: oligodeoxynucleotide . PAI-1: plasminogen activator inhibitor 1 . ROS: reactive oxygen species . TMRM: tetramethylrhodamine . UCP: uncoupling protein . VSMCs: vascular smooth muscle cells