Received for publication July 17, 2008.
Revised November 11, 2008.
Accepted for publication November 12, 2008.

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. As 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, two 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 following 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 due to 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 IRS-1, the p110 catalytic subunit of phosphatidylinositol 3-kinase (PI3K), phosphorylated Akt, and phosphorylated AMP-activated protein kinases (AMPK) in liver, aorta and skeletal muscle. Cumulatively, the results of this study indicate that gene therapy with human eNOS decreased fructose-induced hypertension and insulin resistance in rats, and suggest potential signalling pathways that mediate these effects. These data highlight the potential utility of eNOS gene therapy in the treatment of hypertension and insulin resistance.

Key words: cell signaling pathway, diabetes, endothelial nitric oxide synthase, gene therapy, hypertension, insulin resistanc