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: Arkadi Beloiartsev, Maria da Glória Rodrigues-Machado, Guo Ling Zhou, Timothy C Tan, Luca Zazzeron, Robert E Tainsh, Patricio Leyton, Rosemary C Jones, Marielle Scherrer-Crosbie, Warren M Zapol
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 52 Issue 5 Pg. 563-70 (May 2015) ISSN: 1535-4989 [Electronic] United States
• PMID: 25233285 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hemoglobins
• RNA, Messenger
• Cytochrome P-450 Enzyme System
• CYP2C38 protein, mouse
• Cyp2c29 protein, mouse
• Cytochrome P-450 CYP2J2
• Cytochrome P450 Family 2
• Epoxide Hydrolases
• Ephx2 protein, mouse

Topics

• Animals
• Arterial Pressure
• Cytochrome P-450 CYP2J2
• Cytochrome P-450 Enzyme System (deficiency, genetics, metabolism)
• Cytochrome P450 Family 2
• Disease Models, Animal
• Epoxide Hydrolases (genetics, metabolism)
• Female
• Gene Expression Regulation, Enzymologic
• Genotype
• Hemoglobins (metabolism)
• Hypertension, Pulmonary (enzymology, etiology, genetics, physiopathology)
• Hypertrophy, Right Ventricular (enzymology, etiology)
• Hypoxia (complications)
• Male
• Mice
• Mice, Knockout
• Phenotype
• Pulmonary Artery (enzymology, physiopathology)
• RNA, Messenger (metabolism)
• Time Factors
• Vascular Remodeling