title: Pulmonary hypertension after prolonged hypoxic exposure in mice with a congenital deficiency of Cyp2j.
abstract: Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pulmonary vascular tone and hypoxic pulmonary vasoconstriction. We investigated whether the attenuated acute vasoconstrictor response to hypoxic exposure of Cyp2j(-/-) mice would protect these mice against the pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia. Cyp2j(-/-) and Cyp2j(+/+) male and female mice continuously breathed an inspired oxygen fraction of 0.21 (normoxia) or 0.10 (hypoxia) in a normobaric chamber for 6 weeks. We assessed hemoglobin (Hb) concentrations, right ventricular (RV) systolic pressure (RVSP), and transthoracic echocardiographic parameters (pulmonary acceleration time [PAT] and RV wall thickness). Pulmonary Cyp2c29, Cyp2c38, and sEH mRNA levels were measured in Cyp2j(-/-) and Cyp2j(+/+) male mice. At baseline, Cyp2j(-/-) and Cyp2j(+/+) mice had similar Hb levels and RVSP while breathing air. After 6 weeks of hypoxia, circulating Hb concentrations increased but did not differ between Cyp2j(-/-) and Cyp2j(+/+) mice. Chronic hypoxia increased RVSP in Cyp2j(-/-) and Cyp2j(+/+) mice of either gender. Exposure to chronic hypoxia decreased PAT and increased RV wall thickness in both genotypes and genders to a similar extent. Prolonged exposure to hypoxia produced similar levels of RV hypertrophy in both genotypes of either gender. Pulmonary Cyp2c29, Cyp2c38, and sEH mRNA levels did not differ between Cyp2j(-/-) and Cyp2j(+/+) male mice after breathing at normoxia or hypoxia for 6 weeks. These results suggest that murine Cyp2j deficiency does not attenuate the development of murine pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia in mice of both genders.
authors.affiliation: 1 Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine.
authors.forename: Arkadi
authors.initials: A
authors.lastname: Beloiartsev
authors.forename: Maria
authors.initials: M
authors.lastname: da Glória Rodrigues-Machado
authors.forename: Guo Ling
authors.initials: GL
authors.lastname: Zhou
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Tan
authors.forename: Luca
authors.initials: L
authors.lastname: Zazzeron
authors.forename: Robert E
authors.initials: RE
authors.lastname: Tainsh
authors.forename: Patricio
authors.initials: P
authors.lastname: Leyton
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Jones
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.forename: Warren M
authors.initials: WM
authors.lastname: Zapol
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006454:Hemoglobins / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000209:etiology; D000860:Hypoxia / Q000150:complications*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011651:Pulmonary Artery / Q000201:enzymology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D066253:Vascular Remodeling
chemical_list: D006454:Hemoglobins; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C542274:CYP2C38 protein, mouse; C086292:Cyp2c29 protein, mouse; D000090762:Cytochrome P-450 CYP2J2; D000072467:Cytochrome P450 Family 2; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse
keywords: cytochrome P450 epoxygenases; hypoxia; pulmonary vascular remodeling; right ventricular hypertrophy