Department of Circulatory Medicine, Chaoyang Central Hospital, Chaoyang 122000, China.
Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University, Jinzhou 121001, China.
Can J Physiol Pharmacol. 2021 Sep;99(9):964-973. doi: 10.1139/cjpp-2020-0321. Epub 2021 Feb 27.
Rosuvastatin has been found to possess antioxidant and anti-inflammatory properties. The aim of the current study was to evaluate whether rosuvastatin was effective in attenuating cardiac injury in lipopolysaccharide (LPS) - challenged mice and H9C2 cells and identify the underlying mechanisms, focusing on the nod-like receptor protein 3 (NLRP3)/toll-like receptor 4 (TLR4) pathway. Cardiac injury, cardiac function, apoptosis, oxidative stress, inflammatory response, and the NLRP3/TLR4 pathway were evaluated in both in vivo and in vitro studies. LPS-induced cardiomyocyte injury was markedly attenuated by rosuvastatin treatment, evidenced by increased cell proliferation of H9C2 cells, rescued cardiac function, and improved morphological changes in mice and reduced lactate dehydrogenase (LDH), creatine kinase MB fraction (CK-MB), and troponin I (cTnI) in serum. Apoptosis was clearly ameliorated in myocardial tissue and H9C2 cells co-treated with rosuvastatin. In addition, after LPS challenge, excessive oxidative stress was present, indicated by increases in malondialdehyde (MDA) content, NADPH activity, and reactive oxygen species (ROS) production and decreased superoxide dismutase (SOD) activity. Rosuvastatin improved all the indicators of oxidative stress, with an effect similar to that of -acetylcysteine (NAC) (an ROS scavenger). Notably, LPS-exposed H9C2 cells and mice showed significant NLRP3 and TLR4/nuclear factor-κB (NF-κB) pathway activation and inflammatory responses. Administration of rosuvastatin reduced the increases in NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), pro-caspase-1, TLR4, and p65 expression and decreased the tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-18, and IL-6 contents, with an effect similar to that of MCC950 (an NLRP3 inhibitor). In conclusion, inhibition of the inflammatory response and oxidative stress contributes to cardioprotective effect of rosuvastatin against cardiac injury induced by LPS, and the effect of rosuvastatin was achieved through inactivation of the NF-κB/NLRP3 pathway.
瑞舒伐他汀已被发现具有抗氧化和抗炎特性。本研究旨在评估瑞舒伐他汀是否能有效减轻脂多糖 (LPS) 刺激的小鼠和 H9C2 细胞中的心肌损伤，并确定潜在机制，重点关注核苷酸结合寡聚结构域样受体 3 (NLRP3)/Toll 样受体 4 (TLR4) 途径。在体内和体外研究中评估了心肌损伤、心功能、细胞凋亡、氧化应激、炎症反应和 NLRP3/TLR4 途径。瑞舒伐他汀治疗明显减轻了 LPS 诱导的心肌细胞损伤，这表现在 H9C2 细胞增殖增加、心功能恢复以及小鼠形态学改变改善，同时降低了血清中乳酸脱氢酶 (LDH)、肌酸激酶同工酶 MB 片段 (CK-MB) 和肌钙蛋白 I (cTnI)。心肌组织和共用瑞舒伐他汀处理的 H9C2 细胞中的细胞凋亡明显改善。此外，LPS 刺激后，丙二醛 (MDA) 含量、NADPH 活性、活性氧 (ROS) 生成增加，超氧化物歧化酶 (SOD) 活性降低，表明存在过度氧化应激。瑞舒伐他汀改善了所有氧化应激指标，效果与 ROS 清除剂 N-乙酰半胱氨酸 (NAC) 相似。值得注意的是，暴露于 LPS 的 H9C2 细胞和小鼠表现出明显的 NLRP3 和 TLR4/核因子-κB (NF-κB) 途径激活和炎症反应。瑞舒伐他汀可降低 NLRP3、凋亡相关斑点样蛋白包含半胱氨酸天冬氨酸蛋白酶募集域 (ASC)、前胱天蛋白酶-1、TLR4 和 p65 的表达增加，并降低肿瘤坏死因子 α (TNF-α)、白细胞介素 1β (IL-1β)、白细胞介素 18 (IL-18) 和白细胞介素 6 (IL-6) 的含量，效果与 NLRP3 抑制剂 MCC950 相似。总之，抑制炎症反应和氧化应激有助于瑞舒伐他汀对 LPS 诱导的心肌损伤的心脏保护作用，瑞舒伐他汀的作用是通过 NF-κB/NLRP3 途径失活来实现的。
