Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans

Abstract

It is now well established that obesity is an independent risk factor for the development of coronary artery atherosclerosis. The maintenance of vascular homeostasis is critically dependent on the continued integrity of vascular endothelial cell function. A key early event in the development of atherosclerosis is thought to be endothelial cell dysfunction. A primary feature of endothelial cell dysfunction is the reduced bioavailability of the signalling molecule nitric oxide (NO), which has important anti atherogenic properties. Recent studies have produced persuasive evidence showing the presence of endothelial dysfunction in obese humans NO bioavailability is dependent on the balance between its production by a family of enzymes, the nitric oxide synthases, and its reaction with reactive oxygen species. The endothelial isoform (eNOS) is responsible for a significant amount of the NO produced in the vascular wall. NO production can be modulated in both physiological and pathophysiological settings, by regulation of the activity of eNOS at a transcriptional and post-transcriptional level, by substrate and co-factor provision and through calcium dependent and independent signalling pathways. The present review discusses general mechanisms of reduced NO bioavailability including factors determining production of both NO and reactive oxygen species. We then focus on the potential factors responsible for endothelial dysfunction in obesity and possible therapeutic interventions targetted at thses abnormalities.

Hypoadiponectinemia Is Closely Associated with Impaired Nitric Oxide Synthase Activity in Skeletal Muscle of Type 2 Diabetic Subjects

“…27 Other mechanisms that could explain reduced NO generation in T2DM include increased asymmetric dimethyl arginine (ADMA) levels and decreased cofactors required for synthesis of NO. 28 In cultured bovine aortic endothelial cells, 18,19 adiponectin increases NO production by stimulating eNOS expression/ activity via a PI-3 kinase-dependent pathway involving phosphorylation of eNOS at Ser1179 by AMP-activated protein kinase (AMPK). Conversly, transfection of bovine aortic endothelial cells with dominant-inhibitory mutants of AMPK inhibits NO production in response to adiponectin.…”

Endothelial dysfunction: role in obesity-related disorders and the early origins of CVD

“…Several reports now suggest that obesity impairs vascular function (Williams et al 2002). Obese individuals show an impaired endothelial-mediated vasodilator response to increased blood flow (Arcaro et al 1999), to insulin (Westerbacka et al 1999) and to biochemical agents (Steinberg et al 1996).…”

eNOS haplotype associated with hypertension in obese children and adolescents

“…3 In this context, there is strong evidence that nitric oxide (NO) is critically involved in obesity and its clinical consequences, including cardiovascular disease, diabetes, and especially, hypertension. [4][5][6] Recent studies have shown that obesity reduces NO bioavailability in adolescents, and this alteration has been linked to important cardiovascular diseases. 7,8 Indeed, endothelium-derived NO has a major role in vascular homeostasis, causes vasodilation, prevents platelet and leukocyte adhesion, and inhibits vascular smooth muscle cell migration and proliferation.…”