title: Lentiviral-human heme oxygenase targeting endothelium improved vascular function in angiotensin II animal model of hypertension.
abstract: We examined the hypothesis that vascular and renal dysfunction caused by angiotensin II (Ang II) through increased levels of blood pressure, inflammatory cytokines, and oxidative stress in Sprague-Dawley rats can be prevented by lentiviral-mediated delivery of endothelial heme oxygenase (HO)-1. We targeted the vascular endothelium using a lentiviral construct expressing human HO-1 under the control of the endothelium-specific promoter VE-cadherin (VECAD-HO-1) and examined the effect of long-term human HO-1 expression on blood pressure in Ang II-mediated increases in blood pressure and oxidant stress. A bolus injection of VECAD-HO-1 into the renal artery resulted in expression of human HO-1 for up to 6-9 weeks. Sprague-Dawley rats were implanted with Ang II minipumps and treated with lentivirus carrying either the HO-1 or green fluorescent protein. Renal tissue from VECAD-HO-1-transduced rats expresses human HO-1 mRNA and proteins without an effect on endogenous HO-1. Infusion of Ang II increased blood pressure (p < 0.001) but decreased vascular relaxation in response to acetylcholine, endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) levels, and renal and plasma levels of adiponectin (p < 0.05); in contrast, plasma tumor necrosis factor-α and monocyte chemoattractant protein-1 levels increased. Ang II-treated animals had higher levels of superoxide anion and inducible nitric oxide synthase and increased urinary protein and plasma creatinine levels. Lentiviral transduction with the VECAD-HO-1 construct attenuated the increase in blood pressure (p < 0.05), improved vascular relaxation, increased plasma adiponectin, and prevented the elevation in urinary protein and plasma creatinine in Ang II-treated rats. Endothelial-specific expression of HO-1 also reduced oxidative stress and levels of inflammatory cytokines resulting in increased expression of the anti-apoptotic proteins phosphorylated AKT, phosphorylated AMP-activated protein kinase, peNOS, and eNOS. Collectively, these findings demonstrate that endothelial-specific increases in HO-1 expression attenuate Ang II hypertension and the associated vascular dysfunction that is associated with increases in adiponectin and peNOS and reductions in oxidative stress and levels of inflammatory cytokines.
authors.affiliation: Department of Physiology and Pharmacology, The University of Toledo, Toledo, OH 43614, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.forename: Komal
authors.initials: K
authors.lastname: Sodhi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Inoue
authors.forename: John
authors.initials: J
authors.lastname: Quilley
authors.forename: Rita
authors.initials: R
authors.lastname: Rezzani
authors.forename: Luigi
authors.initials: L
authors.lastname: Rodella
authors.forename: Luca
authors.initials: L
authors.lastname: Vanella
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Germinario
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
authors.forename: Attallah
authors.initials: A
authors.lastname: Kappas
mesh_terms: D052242:Adiponectin / Q000097:blood / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics
chemical_list: D052242:Adiponectin; D015415:Biomarkers; D013481:Superoxides; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D051547:Heme Oxygenase-1