To investigate underlying mechanisms responsible for the impaired nitric oxide (NO)-dependent vascular relaxation in the insulin-resistant state, we examined production of both NO and superoxide anion radical (O2-) and those modulating factors in aortas obtained from normal (CTR), insulin-treated (INS), or high fructose-fed (FR) rats. FR rats showed insulin resistance with endogenous hyperinsulinemia, whereas INS rats showed normal insulin sensitivity. Only FR aortic strips with endothelium elicited impaired relaxation in response to either acetylcholine or calcium ionophore A23187. Endothelial NO synthase (eNOS) activity and its mRNA levels were increased only in vessels from INS rats (P < 0.001), whereas eNOS activity in FR rats was decreased by 58% (P < 0.05) when compared with CTR rats. NO production from aortic strips stimulated with A23187 was significantly lower in FR than CTR rats. In contrast, A23187-stimulated O2- production was higher (P < 0.01) in FR than CTR rats. These differences were abolished when aortic strips were preincubated in the media including (6R)-5,6,7,8-tetrahydrobiopterin (BH4), an active cofactor for eNOS. Furthermore, as compared with CTR rats, aortic BH4 contents in FR rats were decreased (P < 0.001), whereas the levels of 7,8-dihydrobiopterin, the oxidized form of BH4, were increased, with opposite results in INS rats. These results indicate that insulin resistance rather than hyperinsulinemia itself may be a pathogenic factor for decreased vascular relaxation through impaired eNOS activity and increased oxidative breakdown of NO due to enhanced formation of O2- (NO/O2- imbalance), which are caused by relative deficiency of BH4 in vascular endothelial cells.
We have reported that a deficiency of tetrahydrobiopterin (BH(4)), an active cofactor of endothelial NO synthase (eNOS), contributes to the endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O(2)(-)) generation in the insulin-resistant state. To further confirm this hypothesis, we investigated the effects of dietary treatment with BH(4) on endothelium-dependent arterial relaxation and vascular oxidative stress in the aortas of insulin-resistant rats. Oral supplementation of BH(4) (10 mg. kg(-1). d(-1)) for 8 weeks significantly increased the BH(4) content in cardiovascular tissues of rats fed high levels of fructose (fructose-fed rats). Impairment of endothelium-dependent arterial relaxation in the aortic strips of the fructose-fed rats was reversed with BH(4) treatment. The BH(4) treatment was associated with a 2-fold increase in eNOS activity as well as a 70% reduction in endothelial O(2)(-) production compared with those in fructose-fed rats. The BH(4) treatment also partially improved the insulin sensitivity and blood pressure, as well as the serum triglyceride concentration, in the fructose-fed rats. Moreover, BH(4) treatment of the fructose-fed rats markedly reduced the lipid peroxide content of both aortic and cardiac tissues and inhibited the activation of 2 redox-sensitive transcription factors, nuclear factor-kappaB and activating protein-1, which were increased in fructose-fed rats. The BH(4) treatment of control rats did not have any significant effects on these parameters. These results indicate that BH(4) augmentation is essential for the restoration of eNOS function and the reduction of vascular oxidative stress in insulin-resistant rats.
Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. Therefore, augmentation of eNOS expression or NO production by pharmacological intervention is postulated to inhibit atherosclerosis. We crossed eNOS-overexpressing (eNOS-Tg) mice with atherogenic apoE-deficient (apoE-KO) mice to determine whether eNOS overexpression in the endothelium could inhibit the development of atherosclerosis. After 8 weeks on a high-cholesterol diet, the atherosclerotic lesion areas in the aortic sinus were unexpectedly increased by more than twofold in apoE-KO/eNOS-Tg mice compared with apoE-KO mice. Also, aortic tree lesion areas were approximately 50% larger in apoE-KO/eNOS-Tg mice after 12 weeks on a high-cholesterol diet. Expression of eNOS and NO production in aortas from apoE-KO/eNOS-Tg mice were significantly higher than those in apoE-KO mice. However, eNOS dysfunction, demonstrated by lower NO production relative to eNOS expression and enhanced superoxide production in the endothelium, was observed in apoE-KO/eNOS-Tg mice. Supplementation with tetrahydrobiopterin, an NOS cofactor, reduced the atherosclerotic lesion size in apoE-KO/eNOS-Tg mice to the level comparable to apoE-KO mice, possibly through the improvement of eNOS dysfunction. These data demonstrate that chronic overexpression of eNOS does not inhibit, but accelerates, atherosclerosis under hypercholesterolemia and that eNOS dysfunction appears to play important roles in the progression of atherosclerosis in apoE-KO/eNOS-Tg mice.
Anti-programmed cell death-1 (PD-1) antibodies are regarded as a risk factor for insulindependent diabetes mellitus as a side-effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin-dependent diabetes during anti-PD-1 therapy. A 55-year-old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C-peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti-PD-1 therapy can cause rapid onset of insulin-dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti-PD-1 therapy.
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