Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans.
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 these abnormalities.
Williams
I L
IL
Department of Cardiology, Guy's, King's and St Thomas' School of Medicine, King's College London, London, UK. ian.l.Williams@kcl.ac.uk
Wheatcroft
S B
SB
Shah
A M
AM
Kearney
M T
MT
D001161:Arteriosclerosis / Q000209:etiology; D004730:Endothelium, Vascular / Q000503:physiopathology; D006801:Humans; D007333:Insulin Resistance; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009765:Obesity / Q000150:complications / Q000503:physiopathology
D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III