Lentiviral-Human Heme Oxygenase Targeting Endothelium Improved Vascular Function in Angiotensin II Animal Model of Hypertension
- 1 March 2011
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 22 (3), 271-282
- https://doi.org/10.1089/hum.2010.059
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.Keywords
This publication has 72 references indexed in Scilit:
- Physiological significance of heme oxygenase in hypertensionThe International Journal of Biochemistry & Cell Biology, 2009
- L-4F treatment reduces adiposity, increases adiponectin levels, and improves insulin sensitivity in obese miceJournal of Lipid Research, 2008
- Adiponectin regulates albuminuria and podocyte function in miceJCI Insight, 2008
- Pharmacological and Clinical Aspects of Heme OxygenasePharmacological Reviews, 2008
- TNF-α inhibition reduces renal injury in DOCA-salt hypertensive ratsAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2008
- Adiponectin actions in the cardiovascular systemCardiovascular Research, 2007
- Genetic suppression of HO-1 exacerbates renal damage: reversed by an increase in the antiapoptotic signaling pathwayAmerican Journal of Physiology-Renal Physiology, 2007
- Role of Superoxide in Modulating the Renal Effects of Angiotensin IIHypertension, 2003
- Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF-κBBlood, 2003
- Bilirubin inhibits the activation of superoxide-producing NADPH oxidase in a neutrophil cell-free systemBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1991