Abstract
Insulin resistance leads to excessive endothelial cell (EC) superoxide generation and accelerated atherosclerosis. The principal source of superoxide from the insulin-resistant endothelium is the Nox2 isoform of NADPH oxidase. Here we examine the therapeutic potential of Nox2 inhibition on superoxide generation in saphenous vein ECs (SVECs) from patients with advanced atherosclerosis and type 2 diabetes and on vascular function, vascular damage, and lipid deposition in apolipoprotein E-deficient (ApoE−/−) mice with EC-specific insulin resistance (ESMIRO). To examine the effect of genetic inhibition of Nox2, ESMIRO mice deficient in ApoE−/− and Nox2 (ESMIRO/ApoE−/−/Nox2−/y) were generated and compared with ESMIRO/ApoE−/−/Nox2+/y littermates. To examine the effect of pharmacological inhibition of Nox2, we administered gp91dstat or scrambled peptide to ESMIRO/ApoE−/− mice. SVECs from diabetic patients had increased expression of Nox2 protein with concomitant increase in superoxide generation, which could be reduced by the Nox2 inhibitor gp91dstat. After 12 wk Western diet, ESMIRO/ApoE−/−/Nox2−/y mice had reduced EC superoxide generation and greater aortic relaxation to acetylcholine. ESMIRO/ApoE−/−/Nox2−/y mice developed more lipid deposition in the thoraco-abdominal aorta with multiple foci of elastin fragmentation at the level of the aortic sinus and greater expression of intercellular adhesion molecule-1 (ICAM-1). Gp91dstat reduced EC superoxide and lipid deposition in the thoraco-abdominal aorta of ESMIRO/ApoE−/− mice without causing elastin fragmentation or increased ICAM-1 expression. These results demonstrate that insulin resistance is characterized by increased Nox2-derived vascular superoxide. Complete deletion of Nox2 in mice with EC insulin resistance exacerbates, whereas partial pharmacological Nox2 inhibition protects against, insulin resistance-induced vascular damage.
Highlights
Insulin resistant type 2 diabetes is a chronic systemic disorder that leads to deleterious changes in the blood vessel wall [26] and premature cardiovascular disease [1]
Human saphenous vein endothelial cells from patients with diabetes are under oxidative stress due to increased generation of superoxide
Experiments were performed on saphenous vein ECs (SVECs) from a total of 25 patients (20 men, 5 women), who were divided in two groups according to diabetic status: group 1: no diabetes (n ϭ 16), aged 68.1 Ϯ 1.7 yr, range 59 – 83 yr; and group 2: type 2 diabetes (n ϭ 9), aged 66.3 Ϯ 3.8 yr, range 48 –76 yr
Summary
Insulin resistant type 2 diabetes is a chronic systemic disorder that leads to deleterious changes in the blood vessel wall [26] and premature cardiovascular disease [1]. One pathophysiological process thought to make a major contribution to type 2 diabetes-related vascular disease is unrestrained generation of cytotoxic concentrations of the free radical superoxide from the endothelial lining of the arterial wall [2, 9]. This so called “oxidative stress” or “endothelial dysfunction” has a range of effects that could accelerate the development of vascular disease [2], principal among which is thought to be oxidative modification of circulating low-density lipoprotein (LDL), which leads to an adhesion molecule and inflammatory cell-mediated change in the architecture of the arterial wall facilitating subintimal deposition of LDL cholesterol [31]. We showed that inhibition of Nox using pharmacological or genetic approaches can reduce superoxide generation and improve endothelial function in mice with endothelium-specific or whole body insulin resistance [30]
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