title: 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.
authors.affiliation: Department of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong , University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Chun Xia
authors.initials: CX
authors.lastname: Zhao
authors.forename: Xizhen
authors.initials: X
authors.lastname: Xu
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Cui
authors.forename: Peihua
authors.initials: P
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.forename: Shilin
authors.initials: S
authors.lastname: Yang
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D019332:Endothelin-1 / Q000097:blood; D005632:Fructose / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D006946:Hyperinsulinism / Q000201:enzymology / Q000503:physiopathology*; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology*; D007328:Insulin / Q000097:blood; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D014556:Urine / Q000737:chemistry
chemical_list: D019332:Endothelin-1; D007328:Insulin; D012333:RNA, Messenger; D005632:Fructose; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D011494:Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D000091162:AMP-Activated Protein Kinase Kinases