Sex Differences, Estrogen Metabolism and Signaling in the Development of Pulmonary Arterial Hypertension.
Sex Differences, Estrogen Metabolism and Signaling in the Development of Pulmonary Arterial Hypertension.
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肺动脉高压发生过程中的性别差异、雌激素代谢和信号传导
DOI：
10.3389/fcvm.2021.719058
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发表时间：
2021
影响因子：
3.6
通讯作者：
Desai AA
中科院分区：
文献类型：
--
作者：
Sun Y;Sangam S;Guo Q;Wang J;Tang H;Black SM;Desai AA
肺动脉高压(PAH)是一种复杂的破坏性疾病，远期预后较差。虽然女性患PAH的风险增加，但她们表现出优越的右心功能和比男性更高的存活率。PAH对疾病风险的易感性被部分归因于雌激素信号。与雌激素对患者潜在的病理影响相反，动物模型研究显示，雌激素在PAH中具有保护作用。与后一种观察结果一致的是，切除雌性大鼠的卵巢似乎会加剧这种情况。从患者和动物模型观察到的这种差异通常被称为“雌激素悖论”。此外，雌激素、其代谢产物和PAH中的受体与右心功能之间的组织特异性相互作用仍然复杂；然而，这些关系对于更好地了解PAH的病理生理学和潜在地开发新的治疗和治疗靶点是必不可少的。在这篇综述中，我们通过总结已发表的文献，进一步探讨雌激素介导的机制，这些机制可能进一步解释这一悖论：(1)雌激素的合成和分解代谢；(2)各种雌激素受体的活性和功能；(3)细胞内雌激素信号的多种形式；(4)雌激素及其各种代谢产物在PAH易感性和进展中的作用及其对右心功能的影响。
Pulmonary arterial hypertension (PAH) is a complex and devastating disease with a poor long-term prognosis. While women are at increased risk for developing PAH, they exhibit superior right heart function and higher survival rates than men. Susceptibility to disease risk in PAH has been attributed, in part, to estrogen signaling. In contrast to potential pathological influences of estrogen in patients, studies of animal models reveal estrogen demonstrates protective effects in PAH. Consistent with this latter observation, an ovariectomy in female rats appears to aggravate the condition. This discrepancy between observations from patients and animal models is often called the “estrogen paradox.” Further, the tissue-specific interactions between estrogen, its metabolites and receptors in PAH and right heart function remain complex; nonetheless, these relationships are essential to characterize to better understand PAH pathophysiology and to potentially develop novel therapeutic and curative targets. In this review, we explore estrogen-mediated mechanisms that may further explain this paradox by summarizing published literature related to: (1) the synthesis and catabolism of estrogen; (2) activity and functions of the various estrogen receptors; (3) the multiple modalities of estrogen signaling in cells; and (4) the role of estrogen and its diverse metabolites on the susceptibility to, and progression of, PAH as well as their impact on right heart function.