Abstract
Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure, and death. Endothelial dysfunction and inflammation were implicated in the pathogenesis of PAH. Epoxyeicosatrienoic acids (EETs), products of the cytochrome P450 epoxygenase metabolism of arachidonic acid, are potent vasodilators that possess anti-inflammatory and other protective properties in endothelial cells. We investigated whether gene delivery with the human cytochrome P450 epoxygenase 2J2 (CYP2J2) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Significant pulmonary hypertension developed 3 weeks after the administration of MCT, but gene therapy with CYP2J2 significantly attenuated the development of pulmonary hypertension and pulmonary vascular remodeling, without causing changes in systemic arterial pressure or heart rate. These effects were associated with increased pulmonary endothelial NO synthase (eNOS) expression and its activity, inhibition of inflammation in the lungs, and transforming growth factor (TGF)-β/type II bone morphogenetic protein receptor (BMPRII)-drosophila mothers against decapentaplegic proteins (Smads) signaling. Collectively, these data suggest that gene therapy with CYP2J2 may have potential as a novel therapeutic approach to this progressive and oftentimes lethal disorder.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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8,11,14-Eicosatrienoic Acid / analogs & derivatives
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8,11,14-Eicosatrienoic Acid / metabolism
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8,11,14-Eicosatrienoic Acid / urine
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Animals
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Bone Morphogenetic Protein Receptors, Type II / metabolism
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Cytochrome P-450 CYP2J2
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Cytochrome P-450 Enzyme System / genetics*
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Cytochrome P-450 Enzyme System / therapeutic use*
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Endothelial Cells / drug effects
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Endothelial Cells / enzymology
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Gene Transfer Techniques*
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Genetic Therapy*
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Hemodynamics / drug effects
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Humans
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Hypertension, Pulmonary / blood
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Hypertension, Pulmonary / complications
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Hypertension, Pulmonary / physiopathology
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Hypertension, Pulmonary / therapy*
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Hypertrophy, Right Ventricular / blood
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Hypertrophy, Right Ventricular / complications
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Hypertrophy, Right Ventricular / physiopathology
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Hypertrophy, Right Ventricular / urine
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Interleukin-10 / blood
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Interleukin-6 / blood
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Monocrotaline
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NG-Nitroarginine Methyl Ester / pharmacology
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Nitric Oxide Synthase Type III / metabolism
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Pulmonary Artery / drug effects
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Pulmonary Artery / pathology*
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Rats
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Rats, Sprague-Dawley
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Receptors, Platelet-Derived Growth Factor / metabolism
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Signal Transduction / drug effects
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Survival Analysis
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Tissue Extracts / metabolism
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Transforming Growth Factor beta / metabolism
Substances
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14,15-dihydroxyeicosatrienoic acid
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CYP2J2 protein, human
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Interleukin-6
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Tissue Extracts
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Transforming Growth Factor beta
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Interleukin-10
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Monocrotaline
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Cytochrome P-450 Enzyme System
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Nitric Oxide Synthase Type III
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Cytochrome P-450 CYP2J2
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Receptors, Platelet-Derived Growth Factor
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Bone Morphogenetic Protein Receptors, Type II
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8,11,14-Eicosatrienoic Acid
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NG-Nitroarginine Methyl Ester