QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.143396v1 328/2/610    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhao, C. X. Articles by Wang, D. W. Search for Related Content PubMed PubMed Citation Articles by Zhao, C. X. Articles by Wang, D. W.

CARDIOVASCULAR

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

Department of Internal Medicine and the Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China (C.X.Z., X.X., Y.C., P.W., X.W., S.Y., D.W.W.); and Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (M.L.E., D.C.Z.)

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.

Address correspondence to: Dr. Dao Wen Wang, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China. E-mail: dwwang{at}tjh.tjmu.edu.cn