Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Int J Mol Sci. 2020 Jul 15;21(14):4980. doi: 10.3390/ijms21144980.
Investigations of vascular smooth muscle cell (VSMC) phenotypic modulation due to angiotensin II (AngII) stimulation are important for understanding molecular mechanisms contributing to hypertension and associated vascular pathology. AngII induces endoplasmic reticulum (ER) stress in VSMCs, which has been implicated in hypertensive vascular remodeling. Under ER stress, 78 kDa glucose-regulated protein (GRP78) acts as an endogenous chaperone, as well as a master controller of unfolded protein response (UPR) to maintain protein quality control. However, the potential downstream consequences of ER stress induced by AngII on protein quality control and pro-inflammatory phenotype in VSMCs remain elusive. This study aims to identify protein aggregation as evidence of the disruption of protein quality control in VSMCs, and to test the hypothesis that preservation of proteostasis by overexpression of GRP78 can attenuate the AngII-induced pro-inflammatory phenotype in VSMCs. Increases in protein aggregation and enhanced UPR were observed in VSMCs exposed to AngII, which were mitigated by overexpression of GRP78. Moreover, GRP78 overexpression attenuated enhanced monocyte adhesion to VSMCs induced by AngII. Our results thus indicate that the prevention of protein aggregation can potentially mitigate an inflammatory phenotype in VSMCs, which may suggest an alternative therapy for the treatment of AngII-associated vascular disorders.
血管平滑肌细胞（VSMC）由于血管紧张素 II（AngII）刺激而表现型调节的研究对于理解导致高血压和相关血管病理学的分子机制非常重要。AngII 可诱导 VSMC 内质网（ER）应激，这与高血压血管重构有关。在 ER 应激下，78 kDa 葡萄糖调节蛋白（GRP78）作为内源性伴侣，以及未折叠蛋白反应（UPR）的主控制器发挥作用，以维持蛋白质质量控制。然而，AngII 诱导的 ER 应激对 VSMC 中蛋白质质量控制和促炎表型的潜在下游后果仍不清楚。本研究旨在确定蛋白质聚集作为 VSMC 中蛋白质质量控制破坏的证据，并检验以下假设：通过过表达 GRP78 来维持蛋白质稳定性可以减轻 AngII 诱导的 VSMC 促炎表型。在暴露于 AngII 的 VSMC 中观察到蛋白质聚集增加和 UPR 增强，而过表达 GRP78 可减轻这种情况。此外，GRP78 的过表达可减轻 AngII 诱导的单核细胞与 VSMC 的黏附增强。因此，我们的研究结果表明，预防蛋白质聚集可能潜在减轻 VSMC 的炎症表型，这可能为治疗 AngII 相关血管疾病提供一种替代疗法。
