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Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE.

Abstract
We have previously reported that adenoviral-mediated delivery of cytochrome P-450 (CYP) 4A2, which catalyzes the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), results in endothelial dysfunction and hypertension in Sprague-Dawley (SD) rats (Wang JS, Singh H, Zhang F, Ishizuka T, Deng H, Kemp R, Wolin MS, Hintze TH, Abraham NG, Nasjletti A, Laniado-Schwartzman M. Circ Res 98: 962-969, 2006). In this study, we targeted the vascular endothelium by using a lentivirus construct expressing CYP4A2 under the control of the endothelium-specific promoter VE-cadherin (VECAD-4A2) and examined the effect of long-term CYP4A2 overexpression on blood pressure and kidney function in SD rats. A bolus injection of VECAD-4A2 increased blood pressure (P < 0.001) by 26, 36, and 30 mmHg 10, 20, and 30 days postinjection, respectively. Arteries from VECAD-4A2-transduced rats produced increased levels of 20-HETE (P < 0.01), expressed lower levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (p-eNOS) (P < 0.05), generated higher levels of superoxide anion, and displayed decreased relaxing responsiveness to acetylcholine (P < 0.05). Proteinuria increased by twofold in VECAD-4A2-transduced rats compared with controls. Treatment of VECAD-4A2-transduced rats with HET0016, an inhibitor of 20-HETE biosynthesis, not only attenuated the increase in blood pressure (P < 0.05) but also improved vascular function (acetylcholine-induced relaxations) and reduced plasma creatinine and proteinuria. HET0016 treatment decreased oxidative stress and increased the phosphorylated state of key proteins that regulate endothelial function, including eNOS, AKT, and AMPK. Collectively, these findings demonstrate that augmentation of vascular endothelial 20-HETE levels results in hypertension, endothelial dysfunction, and renal injury, which is offset by HET0016 through a reduction in vascular 20-HETE coupled with a lessening of oxidative stress and the amplification of pAKT, pAMPK, and p-eNOS levels leading to normalization of endothelial responses.
AuthorsKazuyoshi Inoue, Komal Sodhi, Nitin Puri, Katherine H Gotlinger, Jiang Cao, Rita Rezzani, John R Falck, Nader G Abraham, Michal Laniado-Schwartzman
JournalAmerican journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 297 Issue 4 Pg. F875-84 (Oct 2009) ISSN: 1522-1466 [Electronic] United States
PMID19675180 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, CD
  • Cadherins
  • DNA, Complementary
  • Hydroxyeicosatetraenoic Acids
  • cadherin 5
  • Superoxides
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Cytochrome P-450 Enzyme System
  • Nitric Oxide Synthase Type III
  • cytochrome P-450 CYP4A2 (rat)
  • AMP-Activated Protein Kinases
  • Proto-Oncogene Proteins c-akt
  • Acetylcholine
Topics
  • AMP-Activated Protein Kinases (metabolism)
  • Acetylcholine
  • Animals
  • Antigens, CD (genetics)
  • Blood Pressure
  • Cadherins (genetics)
  • Cell Line
  • Cytochrome P-450 Enzyme System (genetics, metabolism)
  • DNA, Complementary
  • Endothelium, Vascular (metabolism)
  • Gene Targeting
  • Gene Transfer Techniques
  • Humans
  • Hydroxyeicosatetraenoic Acids (biosynthesis)
  • Hypertension (metabolism)
  • Lentivirus
  • Nitric Oxide Synthase Type III (metabolism)
  • Oxidation-Reduction
  • Phosphorylation
  • Promoter Regions, Genetic
  • Proteinuria (metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Superoxides (metabolism)
  • Vasodilation

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