Inhibition of micro RNA miR-122-5p prevents lipopolysaccharide-induced myocardial injury by inhibiting oxidative stress, inflammation and apoptosis via targeting GIT1.
Inhibition of micro RNA miR-122-5p prevents lipopolysaccharide-induced myocardial injury by inhibiting oxidative stress, inflammation and apoptosis via targeting GIT1.
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DOI：
10.1080/21655979.2021.1926201
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发表时间：
2021-12
期刊：
影响因子：
4.9
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Song W;Zhang T;Yang N;Zhang T;Wen R;Liu C
脓毒症引起的心肌损伤是世界范围内死亡的主要原因。microRNA miR-122- 5 p参与多种生理和病理过程，在脓毒症大鼠心脏中高表达。然而，其在脓毒症引起的心肌损伤中的作用仍然是未知的。本研究通过腹腔注射脂多糖（LPS）建立大鼠脓毒症心肌损伤模型，并将心肌细胞H9 c2暴露于LPS，诱导脓毒症相关的炎性损伤。抑制miR-122- 5 p可抑制LPS引发的心肌损伤，表现为心脏重量指数（HWI）降低、炎性细胞浸润和细胞破裂减少以及心脏标志酶cTnI和LDH降低。miR-122- 5 p抑制LPS处理的大鼠和H9 c2细胞中ROS的产生并增强抗氧化酶CAT、SOD和GSH-px的活性。miR-122- 5 p抑制可减少LPS诱导的促炎细胞因子TNF-α、IL-6和IL-1β的产生，并沿着细胞凋亡和裂解型caspase 3的减少。此外，在miR-122- 5 p抑制后发现GIT 1表达增加。我们进一步验证了GIT 1作为miR-122- 5 p的靶点，并且沉默GIT 1部分逆转了LPS损伤的H9 c2细胞中miR-122- 5 p损失的益处。HO-1和NQO-1表达和Nrf-2激活通过miR-122- 5 p抑制而增强，这通过GIT 1消耗而逆转，表明Nrf-2/HO-1信号转导参与调节miR-122- 5 p/GIT 1介导的心脏保护。综上所述，我们的数据表明，抑制miR-122- 5 p可以通过靶向GIT 1抑制炎症、氧化应激和凋亡来减轻脓毒症触发的心肌损伤，这为脓毒症提供了一个可能的治疗靶点。
Myocardial injury resulting from sepsis is the leading cause of death worldwide. Micro RNA miR-122-5p is involved in various physiological and pathological processes and is highly expressed in the heart of septic rats. However, its function in sepsis-caused myocardial injury remains elusive. Herein, a rat model of septic myocardial injury was established by intraperitoneal injection of lipopolysaccharide (LPS), and cardiomyocyte H9c2 was exposed to LPS to induce sepsis-related inflammatory injury in vitro. Inhibition of miR-122-5p suppressed LPS-triggered myocardial injury evidenced by decreased heart weight index (HWI), reduced inflammatory cell infiltration and cell rupture, and reduced cardiac marker enzymes cTnI and LDH. MiR-122-5p inhibition inhibited ROS production and enhanced the activities of antioxidant enzymes CAT, SOD and GSH-px in LPS-treated rats and H9c2 cells. MiR-122-5p inhibition reduced the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β, and inhibited cell apoptosis along with decreased cleaved-caspase 3 induced by LPS. Moreover, increased GIT1 expression was found following miR-122-5p inhibition. We further verified GIT1 as a target of miR-122-5p, and silencing GIT1 partially reversed the benefits of miR-122-5p loss in LPS-injured H9c2 cells. The HO-1 and NQO-1 expression and Nrf-2 activation were enhanced by miR-122-5p inhibition, which was reversed by GIT1 depletion, indicating the involvement of Nrf-2/HO-1 signaling in regulating miR-122-5p/GIT1-mediated cardioprotection. Taken together, our data suggest that inhibition of miR-122-5p may mitigate sepsis-triggered myocardial injury through inhibiting inflammation, oxidative stress and apoptosis via targeting GIT1, which provides a possible therapeutic target for sepsis.
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