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.
Footnotes
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This research was supported in part by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Grant Z01 ES025034]; by the National 863 Plan Project [Grant 2004AA217121]; the National Education Ministration Project and Nature Science Foundation Committee Project [Grants 30540087, 30700377]; and the 973 program [Grant 2007CB512004].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.143396.
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ABBREVIATIONS: NO, nitric oxide; eNOS, endothelial nitric-oxide synthase; PI3K, phosphatidylinositol 3-kinase; Akt, cellular homolog of the v-alt oncogene, an S/T protein kinase; PKB, protein kinase B; p, phosphorylated; AMPK, AMP-activated protein kinase; MAPK, mitogen-activated protein kinase; IRS, insulin receptor substrate; N, normal; F, fructose; HOMA-IR, homeostasis model assessment-insulin resistance; ET, endothelin; PCR, polymerase chain reaction; ETA-R, endothelin receptor A; NOx, nitrite + nitrate.
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↵1 Current affiliation: Department of Internal Medicine, Jining Affiliated Hospital of Jining Medical College, Jining, Shandong Province, People's Republic of China.
- Received July 10, 2008.
- Accepted November 12, 2008.
- U.S. Government work not protected by U.S. copyright
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