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首页> 外文期刊>Pulmonary Circulation >Cyp2c44 Gene Disruption Exacerbated Pulmonary Hypertension and Heart Failure in Female but Not Male Mice:
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Cyp2c44 Gene Disruption Exacerbated Pulmonary Hypertension and Heart Failure in Female but Not Male Mice:

机译：Cyp2c44基因破坏加剧了女性而非男性小鼠的肺动脉高压和心力衰竭：

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Epoxyeicosatrienoicacids (EETs), synthesized from arachidonic acid by epoxygenases of the CYP2C and CYP2J gene subfamilies, contribute to hypoxic pulmonary vasoconstriction (HPV) in mice. Despite their roles in HPV, it is controversial whether EETs mediate or ameliorate pulmonary hypertension (PH). A recent study showed that deficiency of Cyp2j did not protect male and female mice from hypoxia-induced PH. Since CYP2C44 is a functionally important epoxygenase, we hypothesized that knockout of the Cyp2c44 gene would protect both sexes of mice from hypoxia-induced PH. We tested this hypothesis in wild-type (WT) and Cyp2c44 knockout (Cyp2c44?/?) mice exposed to normoxia (room air) and hypoxia (10% O2) for 5 weeks. Exposure of WT and Cyp2c44?/? mice to hypoxia resulted in pulmonary vascular remodeling, increased pulmonary artery resistance, and decreased cardiac function in both sexes. However, in female Cyp2c44?/? mice, compared with WT mice, (1) pulmonary artery resistance and right ventricular hypertrophy were greater, (2) cardiac index was lower, (3) left ventricular and arterial stiffness were higher, and (4) plasma aldosterone levels were higher, but (5) there was no difference in levels of EET in lungs and heart. Paradoxically and unexpectedly, we found that Cyp2c44 disruption exacerbated hypoxia-induced PH in female but not male mice. We attribute exacerbated PH in female Cyp2c44?/? mice to elevated aldosterone and as-yet-unknown systemic factors. Therefore, we suggest a role for the human CYP2C genes in protecting women from severe PH and that this could be one of the underlying causes for a better 5-year survival rate in women than in men.
机译：环氧二十碳三烯酸（EET）是由花生四烯酸通过CYP2C和CYP2J基因亚家族的环氧合酶合成的，有助于小鼠缺氧性肺血管收缩（HPV）。尽管它们在HPV中发挥作用，但EET是否介导或减轻肺动脉高压（PH）仍存在争议。最近的一项研究表明，Cyp2j的缺乏不能保护雄性和雌性小鼠免受缺氧诱导的PH的影响。由于CYP2C44是功能上重要的环氧合酶，我们假设敲除Cyp2c44基因将保护小鼠的两性免于低氧诱导的PH。我们在暴露于常氧（室内空气）和低氧（10％O2）5周的野生型（WT）和Cyp2c44基因敲除（Cyp2c44？/？）小鼠中测试了这一假设。 WT和Cyp2c44？/？的暴露缺氧的小鼠导致两性的肺血管重构，肺动脉阻力增加和心脏功能下降。但是，在女性Cyp2c44中？与WT小鼠相比，（1）肺动脉阻力和右心室肥大较大，（2）心脏指数较低，（3）左心室和动脉僵硬度较高，（4）血浆醛固酮水平较高，但是（5）肺和心脏的EET水平没有差异。矛盾的是，我们意外地发现，Cyp2c44破坏加剧了雌性小鼠的缺氧诱导的PH，但雄性小鼠却没有。我们将雌性Cyp2c44？/？中加重的PH归因于小鼠体内醛固酮水平升高和迄今未知的全身性因素。因此，我们建议人类CYP2C基因在保护女性免受严重PH的作用，这可能是女性比男性高5年生存率的根本原因之一。

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