Redox and Inflammatory Signaling, the Unfolded Protein Response, and the Pathogenesis of Pulmonary Hypertension
Redox and Inflammatory Signaling, the Unfolded Protein Response, and the Pathogenesis of Pulmonary Hypertension
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DOI：
10.1007/978-3-030-68748-9_17
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发表时间：
2021-01-01
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影响因子：
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通讯作者：
Wolin, Michael S.
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文献类型：
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作者：
Katseff, Adiya;Alhawaj, Raed;Wolin, Michael S.
蛋白质折叠过载和氧化应激破坏内质网（ER）的稳态，产生活性氧（ROS）并激活未折叠蛋白反应（UPR）。改变的ER氧化还原状态通过UPR信号传导诱导进一步的ROS产生，所述UPR信号传导平衡存活和凋亡的细胞命运，导致肺微血管炎症和功能障碍并驱动肺动脉高压（PH）的发展。UPR诱导的ROS产生通过ER钙释放沿着NADPH氧化酶活性导致内皮损伤和平滑肌细胞（SMC）增殖。ROS和钙信号还促进内皮型一氧化氮合酶（eNOS）解偶联，通过持续的血管收缩和SMC增殖减少NO产生并增加血管阻力。C/EBP同源蛋白进一步抑制eNOS，干扰内皮功能。UPR诱导的NF-B活性调节肺组织中的炎症过程并有助于肺血管重塑。相反，UPR激活的核因子红细胞2相关因子2通过血红素加氧酶1介导的抗氧化信号传导可降低炎症细胞因子水平并防止血管SMC增殖。骨形态发生蛋白2型受体（BMPR 2）基因突变导致错误折叠的BMPR 2蛋白在ER中积聚，暗示UPR在家族性肺动脉高压发病机制中。总之，有大量的证据表明，氧化还原和炎症信号与UPR激活是至关重要的PH发病机制。
Protein folding overload and oxidative stress disrupt endoplasmic reticulum (ER) homeostasis, generating reactive oxygen species (ROS) and activating the unfolded protein response (UPR). The altered ER redox state induces further ROS production through UPR signaling that balances the cell fates of survival and apoptosis, contributing to pulmonary microvascular inflammation and dysfunction and driving the development of pulmonary hypertension (PH). UPR-induced ROS production through ER calcium release along with NADPH oxidase activity results in endothelial injury and smooth muscle cell (SMC) proliferation. ROS and calcium signaling also promote endothelial nitric oxide (NO) synthase (eNOS) uncoupling, decreasing NO production and increasing vascular resistance through persistent vasoconstriction and SMC proliferation. C/EBP-homologous protein further inhibits eNOS, interfering with endothelial function. UPR-induced NF-.B activity regulates inflammatory processes in lung tissue and contributes to pulmonary vascular remodeling. Conversely, UPR-activated nuclear factor erythroid 2-related factor 2-mediated antioxidant signaling through heme oxygenase 1 attenuates inflammatory cytokine levels and protects against vascular SMC proliferation. A mutation in the bone morphogenic protein type 2 receptor (BMPR2) gene causes misfolded BMPR2 protein accumulation in the ER, implicating the UPR in familial pulmonary arterial hypertension pathogenesis. Altogether, there is substantial evidence that redox and inflammatory signaling associated with UPR activation is critical in PH pathogenesis.