Division of Pulmonary, and Critical Care Medicine, Department of Pediatrics, University of Colorado at Denver, Aurora, 80138, USA.
Am J Respir Cell Mol Biol. 2012 Jan;46(1):14-22. doi: 10.1165/rcmb.2010-0506OC.
Endothelin-1 is a potent vasoactive peptide that occurs in chronically high levels in humans with pulmonary hypertension and in animal models of the disease. Recently, the unfolded protein response was implicated in a variety of diseases, including pulmonary hypertension. In addition, evidence is increasing for pathological, persistent inflammation in the pathobiology of this disease. We investigated whether endothelin-1 might engage the unfolded protein response and thus link inflammation and the production of hyaluronic acid by pulmonary artery smooth muscle cells. Using immunoblot, real-time PCR, immunofluorescence, and luciferase assays, we found that endothelin-1 induces both a transcriptional and posttranslational activation of the three major arms of the unfolded protein response. The pharmacologic blockade of endothelin A receptors, but not endothelin B receptors, attenuated the observed release, as did a pharmacologic blockade of extracellular signal-regulated kinases 1 and 2 (ERK-1/2) signaling. Using short hairpin RNA and ELISA, we observed that the release by pulmonary artery smooth muscle cells of inflammatory modulators, including hyaluronic acid, is associated with endothelin-1-induced ERK-1/2 phosphorylation and the unfolded protein response. Furthermore, the synthesis of hyaluronic acid induced by endothelin-1 is permissive for persistent THP-1 monocyte binding. These results suggest that endothelin-1, in part because it induces the unfolded protein response in pulmonary artery smooth muscle cells, triggers proinflammatory processes that likely contribute to vascular remodeling in pulmonary hypertension.
内皮素-1 是一种强效血管活性肽，在患有肺动脉高压的人类和疾病动物模型中持续处于高水平。最近， unfolded protein response（未折叠蛋白反应）被牵涉到多种疾病中，包括肺动脉高压。此外，越来越多的证据表明，在这种疾病的病理生物学中存在病理性、持续性炎症。我们研究了内皮素-1 是否可能参与 unfolded protein response（未折叠蛋白反应），从而将炎症与肺血管平滑肌细胞中透明质酸的产生联系起来。通过免疫印迹、实时 PCR、免疫荧光和荧光素酶测定，我们发现内皮素-1 诱导 unfolded protein response（未折叠蛋白反应）的三个主要分支的转录和翻译后激活。内皮素 A 受体的药理学阻断，但不是内皮素 B 受体的阻断，减弱了观察到的释放，而细胞外信号调节激酶 1 和 2（ERK-1/2）信号的药理学阻断也是如此。通过短发夹 RNA 和 ELISA，我们观察到肺血管平滑肌细胞释放炎症调节剂，包括透明质酸，与内皮素-1 诱导的 ERK-1/2 磷酸化和 unfolded protein response（未折叠蛋白反应）有关。此外，内皮素-1 诱导的透明质酸合成允许持续的 THP-1 单核细胞结合。这些结果表明，内皮素-1 部分是因为它诱导肺血管平滑肌细胞中的 unfolded protein response（未折叠蛋白反应），引发了可能导致肺动脉高压血管重塑的促炎过程。
