Increased Endothelial Nitric-Oxide Synthase Expression Reduces Hypertension and Hyperinsulinemia in Fructose-Treated Rats

Abstract

Endothelial dysfunction and decreased production of nitric oxide (NO) by endothelial NO synthase (eNOS) are implicated in the pathogenesis of hypertension and insulin resistance. Because the potential influence of increased eNOS expression/ activity on these parameters is unclear, the present study examined the effects of eNOS gene therapy on insulin resistance and blood pressure alterations in a fructose-induced hypertension model in rats. As predicted, 2 weeks of fructose consumption in the drinking water resulted in elevated systolic blood pressure and insulin resistance. These and other physiologic alterations were reversed within 2 weeks after a single intravenous injection of a vector containing the human eNOS cDNA (pcDNA3.1-eNOS), whereas injection of an empty vector (pcDNA3.1) was without effect. In support of the beneficial effects of pcDNA3.1-eNOS treatment being because of enhanced eNOS expression and activity, increased eNOS protein levels were documented in aorta, liver, kidney, and heart of fructose-treated rats injected with pcDNA3.1-eNOS, and corresponding elevations in nitrite/nitrate and cGMP concentrations were observed in urine. Furthermore, pcDNA3.1-eNOS treatment prevented fructose-induced decreases in expression levels of insulin receptor substrate-1, the p110 catalytic subunit of phosphatidylinositol 3-kinase, phosphorylated Akt, and phosphorylated AMP-activated protein kinases in liver, aorta, and skeletal muscle. The results of this study cumulatively indicate that gene therapy with human eNOS decreased fructose-induced hypertension and insulin resistance in rats and suggest potential signaling pathways that mediate these effects. These data highlight the potential utility of eNOS gene therapy in the treatment of hypertension and insulin resistance.Nitric oxide (NO), a potent vasodilator constitutively produced by endothelial nitric-oxide synthase (eNOS), is thought to be the endothelium-derived relaxing factor that mediates relaxation in response to acetylcholine, bradykinin, and substance P in vascular beds (Rees and Moncada, 1989). eNOS is the predominant vascular NO synthase isoform and is responsible for the majority of NO production in the vasculature (Moncada and Higgs, 2006). In addition to its effects on the regulation of blood pressure and regional blood flow, NO influences vascular smooth muscle proliferation and inhibits platelet aggregation and leukocyte adhesion (Moncada and Higgs, 2006).A number of lines of evidence implicate eNOS-derived NO as a pivotal regulator of blood pressure, vascular tone, and vascular homeostasis. In vivo inhibition of NO synthase activity by nonhydrolyzable analogs of L-arginine results in a dramatic increase in mean arterial blood pressure (Desjardins and Balligand, 2006), whereas mice genetically deficient in eNOS have impaired endothelium-dependent vasodilator responses to acetylcholine and are hypertensive (Huang et

Increased Fructose Associates with Elevated Blood Pressure

“…16 Recently, Nguyen et al 14 showed an association among sugarsweetened beverages, serum uric acid levels, and SBP in a crosssectional analysis of 4867 adolescents who were between the ages of 12 and 18 years and had participated in the NHANES (1999 to 2004). Studies in animals suggested that fructose may raise BP via several mechanisms, including stimulation of uric acid, [17][18][19] inhibition of endothelial nitric oxide synthase system, 20,21 and stimulation of the sympathetic nervous system, 22 or by directly increasing sodium absorption in the gut. 23 Although uric acid has been shown to mediate fructose-induced hypertension in rats, we could not demonstrate a relationship between high fructose intake and serum uric acid levels in this study.…”

Matsuda–DeFronzo insulin sensitivity index is a better predictor than HOMA-IR of hypertension in Japanese: the Tanno–Sobetsu study

“…5,[47][48][49] Thus, the finding that association of ISI-M with new-onset hypertension in the multiple logistic regression analysis was lost by incorporating BMI as a dependent variable (Table 4) does not necessarily exclude the possibility that IR per se contributes to the development of hypertension. In fact, OR of hypertension was higher in a subgroup with lower ISI-M than in a subgroup with higher ISI-M for each tertile of BMI in subjects o60 years old (Figure 3), whereas higher BMI was associated with higher OR of hypertension.…”

“…5,[13][14][15][47][48][49][50] However, the contribution of any of these mechanisms has not yet been unequivocally demonstrated in human subjects. Acute hyperinsulinemia, induced by insulin infusion, has been shown to reduce urinary sodium excretion and to increase plasma norpeinephrine and renin activity, but it does not consistently elevate BP.…”

Endothelial Nitric Oxide Synthase (eNOS) Glu298Asp Gene Polymorphism (G894T) as a Risk Factor for Type 2 Diabetes Mellitus in the Tunisian Population

“…Indeed, endothelial dysfunction and decreased production of nitric oxide (NO) by endothelial NO synthase (eNOS) is involved in the pathogenesis of insulin resistance and hypertension [21]. The polymorphic variants of the eNOS gene are associated with high blood pressure and insulin resistance in different populations [22].…”