BACKGROUND The mechanisms involved in pulmonary hypertension (PH) development in patients and pre-clinical models are poorly understood. PH has a well-established sex dimorphism in patients with increased frequency of PH in females, and more severe disease with poor survival prognosis in males. Previously, we found that heme signaling plays an essential role in the development phase of the Sugen/Hypoxia (SU/Hx) model. This study is focused on the elucidation of sex differences in mechanisms of PH development related to heme action at the early stage of the monocrotaline (MCT) PH model. METHODS Rats received MCT injection (60 mg/kg, i.p.) and followed for 14 days to investigate early disease changes. Hemodynamic parameters were recorded at the end of the study; plasma, lung homogenates, and nuclear fractions were used for the evaluation of protein levels. RESULTS Our data indicate that on day 14, rats did not show any significant increase in the Fulton index due to the early disease phase. However, the right ventricular systolic pressure was significantly increased in male rats, while female rats showed only a trend. Interestingly, only males demonstrated an increased lung-to-bodyweight ratio that indicated lung edema. Indeed, lung histology confirmed severe perivascular edema in males. Previously, we have reported that the increased perivascular edema in SU/Hx model correlated with intravascular hemolysis and activated heme signaling. Here, we found that elevated free hemoglobin levels and perivascular edema were increased, specifically in males showing more rapid progress of PH. A high level of heme carrier protein 1 (HCP-1), which is involved in heme uptake from the bloodstream into the cells, was also found elevated in the lungs of males. The upregulation of heme oxygenase in males indicated increased intracellular heme catabolism. Increased heme signaling resulted in the activation of heme-mediated barrier-disruptive mechanisms. Thus, hemolysis in males can be responsible for increased permeability of the lungs and early disease development. CONCLUSIONS Our study indicates the importance of barrier-disruptive mechanisms as an earlier event in the induction of pulmonary hypertension. Importantly, males are more susceptible to hemolysis and develop PH earlier than females.

中文翻译：

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男性在单crocrotaline模型中肺动脉高压的早期进展与肺通透性增加有关。

背景技术与患者肺动脉高压（PH）发展有关的机制和临床前模型知之甚少。在女性中，PH频发的患者中，PH具有公认的性别二态性，而在男性中，PH较严重的疾病具有较差的生存预后。以前，我们发现血红素信号传导在Sugen / Hypoxia（SU / Hx）模型的开发阶段起着至关重要的作用。这项研究的重点是阐明在单crocrotaline（MCT）PH模型早期与血红素作用有关的PH发育机制中的性别差异。方法大鼠接受MCT注射（60 mg / kg，腹腔注射），并随访14天以研究早期疾病变化。在研究结束时记录血流动力学参数；血浆，肺匀浆 核级分用于评估蛋白质水平。结果我们的数据表明，在第14天，由于疾病早期，大鼠的Fulton指数未显示任何明显增加。然而，雄性大鼠的右心室收缩压显着增加，而雌性大鼠仅表现出趋势。有趣的是，只有男性表现出增加的肺与体重之比，表明肺水肿。确实，肺组织学证实了男性严重的血管周围水肿。以前，我们已经报道SU / Hx模型中血管周围水肿的增加与血管内溶血和激活的血红素信号有关。在这里，我们发现升高的游离血红蛋白水平和血管周水肿增加，特别是在显示PH更快进展的男性中。高水平的血红素载体蛋白1（HCP-1），男性肺部血红蛋白升高也与血红素的吸收有关。男性血红素加氧酶的上调表明细胞内血红素分解代谢增加。血红素信号的增加导致血红素介导的屏障破坏机制的激活。因此，男性的溶血可能是导致肺通透性增加和疾病早期发展的原因。结论我们的研究表明屏障破坏机制作为诱发肺动脉高压的早期事件的重要性。重要的是，男性比女性更容易发生溶血，并较早出现PH。男性血红素加氧酶的上调表明细胞内血红素分解代谢增加。血红素信号的增加导致血红素介导的屏障破坏机制的激活。因此，男性的溶血可能是导致肺通透性增加和疾病早期发展的原因。结论我们的研究表明屏障破坏机制作为诱发肺动脉高压的早期事件的重要性。重要的是，男性比女性更容易发生溶血，并较早出现PH。男性血红素加氧酶的上调表明细胞内血红素分解代谢增加。血红素信号的增加导致血红素介导的屏障破坏机制的激活。因此，男性的溶血可能是导致肺通透性增加和疾病早期发展的原因。结论我们的研究表明屏障破坏机制作为诱发肺动脉高压的早期事件的重要性。重要的是，男性比女性更容易溶血并且更容易发生PH。结论我们的研究表明屏障破坏机制作为诱发肺动脉高压的早期事件的重要性。重要的是，男性比女性更容易发生溶血，并较早出现PH。结论我们的研究表明屏障破坏机制作为诱发肺动脉高压的早期事件的重要性。重要的是，男性比女性更容易发生溶血，并较早出现PH。