Tian Jiayu, Niu Zeyu, Yang Huan, Wang Caihong, Guan Linlin, Zhao Lifang, Shi Dongxing, Zhang Zhihong
Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan 030001, China.
Yellow River Basin Ecological Public Health Security Center, Shanxi Medical University, 56 Xinjian South Road, Taiyuan 030001, China.
Int J Mol Sci. 2025 Apr 17;26(8):3784. doi: 10.3390/ijms26083784.
Although the strong causal association between PM and cardiovascular disease has been extensively studied, the latent molecular mechanisms have not been entirely explained. The objective of this research was to assess the cardiotoxicity of Traffic-related PM (TRPM), water-soluble components (WSC), and water-insoluble components (WIC) in human cardiomyocytes (AC16) and to investigate the underlying molecular mechanisms. Endoplasmic reticulum stress (ERS), autophagy, and apoptosis were activated 24 h after exposure to total-TRPM, WSC, or WIC. WIC was predominantly related to cardiotoxicity compared to WSC. Sestrin2 is an upstream molecule in several signaling pathways, including those involved in autophagy and apoptosis. In this study, we found that the knockdown of Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) suppressed the expression of PERK, Sestrin2, Caspase-12, Caspase-3, LC3, and p62 in TRPM-treated AC16 cells. These results indicate that ERS participates in the activation of autophagy and apoptosis through the PERK/Sestrin2 pathway. We found that inhibiting autophagy with 3-methyladenine (3-MA) decreased the expression of autophagy-related factors and aggravated apoptosis. These observations suggest that protective autophagy was initiated. Finally, our findings provide valuable insights into the molecular mechanism by which ERS might regulate autophagy through the PERK/Sestrin2 signaling pathway, and protective autophagy may be activated to relieve TRPM and component-mediated apoptosis in AC16 cells.
尽管已对细颗粒物（PM）与心血管疾病之间强烈的因果关联进行了广泛研究，但潜在的分子机制尚未完全阐明。本研究的目的是评估交通相关细颗粒物（TRPM）、水溶性成分（WSC）和水不溶性成分（WIC）对人心肌细胞（AC16）的心脏毒性，并探究其潜在分子机制。暴露于总TRPM、WSC或WIC 24小时后，内质网应激（ERS）、自噬和凋亡被激活。与WSC相比，WIC主要与心脏毒性相关。 sestrin2是包括自噬和凋亡相关信号通路在内的多个信号通路的上游分子。在本研究中，我们发现敲低蛋白激酶RNA样内质网激酶（PERK）可抑制TRPM处理的AC16细胞中PERK、sestrin2、半胱天冬酶-12、半胱天冬酶-3、微管相关蛋白1轻链3（LC3）和p62的表达。这些结果表明，ERS通过PERK/sestrin2通路参与自噬和凋亡的激活。我们发现用3-甲基腺嘌呤（3-MA）抑制自噬可降低自噬相关因子的表达并加重凋亡。这些观察结果提示启动了保护性自噬。最后，我们的研究结果为ERS可能通过PERK/sestrin2信号通路调节自噬的分子机制提供了有价值的见解，并且可能激活保护性自噬以减轻TRPM及其成分介导的AC16细胞凋亡。
