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 2/2 mice would protect these mice against the pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia. Cyp2j 2/2 and Cyp2j 1/1 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 2/2 and Cyp2j 1/1 male mice. At baseline, Cyp2j 2/2 and Cyp2j 1/1 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 2/2 and Cyp2j 1/1 mice. Chronic hypoxia increased RVSP in Cyp2j 2/2 and Cyp2j 1/1 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 2/2 and Cyp2j 1/1 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.Keywords: hypoxia; cytochrome P450 epoxygenases; pulmonary vascular remodeling; right ventricular hypertrophy Pulmonary hypertension (PH) due to increased vascular tone in lung vessels is important in many acute and chronic lung diseases, such as pulmonary embolism and idiopathic pulmonary arterial hypertension. Although progress has been made with therapeutic approaches to reduce vascular tone, all of the pathways influencing lung vascular tone have not been fully explored.

Cyp2c44 Gene Disruption Exacerbated Pulmonary Hypertension and Heart Failure in Female but Not Male Mice

“…Although it was recently found that Cyp2j deficiency does not attenuate hypoxia-induced PH in male and female mice, we now demonstrate that knockout of CYP2C44 epoxygenase, which metabolizes arachidonic acid predominantly to EETs, increases the severity of PH and heart failure in female but not male mice. 24…”

“…acid predominantly to EETs, increases the severity of PH and heart failure in female but not male mice. 24 CYP2C44 has little homology with other mouse CYP2C expoxygenases but is highly homologous to the rat kidney CYP2C23. 19 CYP2C44 is predominantly expressed in liver, kidneys, and adrenal glands.…”

“…21 In contrast, monocrotaline-induced inflammation and PH in rats are ameliorated by inhibition of soluble epoxide hydrolase and overexpression of the Cyp2j5 gene, 22,23 whereas deletion of the Cyp2j gene locus does not attenuate the hypoxia-elicited pulmonary artery remodeling and hypertension in male and female mice. 24 CYP2C29 and CYP2J5 are equally expressed in hepatic and extrahepatic tissues of both sexes, whereas CYP2C44 is expressed more in the kidneys and adrenal glands of female mice than male mice. [18][19][20] Since CYP2C44 shows a sex preference, we postulated that differential regulation of CYP2C44 expression and activity could play a role in mediating less severe PH in females versus males.…”

Detection and removal of impurities in nitric oxide generated from air by pulsed electrical discharge

“…Tissues were perfused with 3% paraformaldehyde and 0.1% glutaraldehyde in PBS and fixed in the same solution for 24 hrs. Paraffin-embedded sections of 3–4 µm thickness were stained with hematoxylin and eosin [20; 21]. Digital images of the lung tissue were acquired via bright field microscopy (Elipse 80i, Nikon Instruments Inc., Melville, NY).…”

Reciprocal actions of constrictor prostanoids and superoxide in chronic hypoxia‐induced pulmonary hypertension: roles of EETs

“…7 Alternatively, others reported significant downregulation of pulmonary CYP2C29 and CYP2C38 mRNA associated with unchanged sEH expression after exposure of mice to hypoxia for six weeks. 28 These controversies suggest that different regimens of hypoxic treatment may evoke divergent mechanisms and yield specific phenotypes. To date, even though the lack of consensus for whether the increase in EET synthesis and decrease in EET hydrolysis are only relevant to HPH, or universally applicable to other types of PH, our studies, as well as others have clarified hypoxia-potentiation of EET bioavailability.…”