Malfunction of vascular control in lifestyle-related diseases: mechanisms underlying endothelial dysfunction in the insulin-resistant state.
It is tempting to speculate that increased vasoconstriction and loss of endothelium-dependent vasodilation might be etiological factors of elevated blood pressure in the insulin-resistant state. Vascular contraction induced by angiotensin II and the expression of NAD(P)H oxidase were increased in the aorta of insulin-resistant mice. In addition, both angiotensin II type 1 receptor expression and superoxide anion production were up-regulated in these mice. Another mechanism for imparing endothelial function is the uncoupling of endothelial nitric oxide synthase (eNOS). It has become clear from studies on the aorta of insulin-resistant rat that insulin resistance may be a pathogenic factor for endothelial dysfunction through impaired eNOS activity and increased oxidative breakdown of NO (nitric oxide) due to an enhanced formation of superoxide anion (NO/superoxide anion imbalance), which are caused by relative deficiency of tetrahydrobiopterin, a cofactor of NOS, in vascular endothelial cells. Supplementation of tetrahydrobiopterin restored endothelial function and relieved oxidative tissue damage through activation of eNOS in those rats. These results indicate that generation of superoxide anion from NAD(P)H oxidases and an uncoupled eNOS may be pathogenic factors for impaired endothelial function and hypertension in the insulin-resistant state.
Shinozaki
Kazuya
K
Department of Pharmacology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Ayajiki
Kazuhide
K
Kashiwagi
Atsunori
A
Masada
Masahiro
M
Okamura
Tomio
T
D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D007333:Insulin Resistance; D019255:NADPH Oxidases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D012084:Renin-Angiotensin System / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
D013481:Superoxides; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases