球形 CTRP9 通过增强自噬流来保护心肌细胞免受棕榈酸诱导的氧化应激。
Globular CTRP9 protects cardiomyocytes from palmitic acid-induced oxidative stress by enhancing autophagic flux.
机构信息
Department of General Medicine, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China; Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.
出版信息
Chem Biol Interact. 2020 Sep 25;329:109094. doi: 10.1016/j.cbi.2020.109094. Epub 2020 Apr 10.
BACKGROUND
Oxidative stress in cardiac myocytes is an important pathogenesis of cardiac lipotoxicity. Autophagy is a cellular self-digestion process that can selectively remove damaged organelles under oxidative stress, and thus presents a potential therapeutic target against cardiac lipotoxicity. Globular CTRP9 (gCTRP9) is a newly identified adiponectin paralog with established metabolic regulatory properties. The aim of this work is to investigate whether autophagy participates the protection effects of gCTRP9 in neonatal rat cardiac myocytes (NRCMs) under oxidative stress and the underlying mechanism.
RESULTS
NRCMs were treated with PA of various concentrations for indicated time period. Our results showed that PA enhanced intracellular ROS accumulation, decreased mitochondrial membrane potential (Δψm) and increased activation of caspases 3. These changes suggested lipotoxicity due to excessive PA. In addition, PA was observed to impair autophagic flux in NRCMs and impaired autophagosome clearance induced by PA contributes to cardiomyocyte death. Besides, we found that gCTRP9 increased the ratio of LC3II/I and the expression of ATG5 which was vital to the formation of autophagosomes and decreased the level of P62, suggesting enhanced autophagic flux in the absence or presence of PA. The result was further confirmed by the methods of infection with LC3-mRFP-GFP lentivirus and blockage of autophagosome-lysosome fusion by BafA1. Moreover, gCTRP9 reestablished the loss of mitochondrial membrane potential, suppressed ROS generation, and reduced PA -induced myocyte death. However, the protective effect of gCTRP9 on the cardiac lipotoxicity was partly abolished by blockade of autophagy by autophagy-related 5 (ATG5) siRNA, indicating that the effect of gCTRP9 on cell survival is critically mediated through regulation of autophagy.
CONCLUSION
Autophagy induction by gCTRP9 could be utilized as a potential therapeutic strategy against oxidative stress-mediated damage in cardiomyocytes.
背景
心肌细胞中的氧化应激是心脏脂肪毒性的重要发病机制。自噬是一种细胞自我消化过程，可以在氧化应激下选择性地清除受损的细胞器，因此成为治疗心脏脂肪毒性的潜在靶点。球形 C 型趋化因子受体 9（gCTRP9）是一种新发现的脂联素旁系同源物，具有明确的代谢调节特性。本研究旨在探讨自噬是否参与 gCTRP9 在氧化应激下对新生大鼠心肌细胞（NRCMs）的保护作用及其机制。
结果
用不同浓度的 PA 处理 NRCMs 一段时间。结果显示，PA 增强了细胞内 ROS 的积累，降低了线粒体膜电位（Δψm），并增加了 caspase 3 的激活。这些变化提示由于 PA 过量导致了脂肪毒性。此外，PA 被观察到损害 NRCMs 中的自噬流，而 PA 诱导的自噬体清除受损导致心肌细胞死亡。此外，我们发现 gCTRP9 增加了 LC3II/I 的比值和 ATG5 的表达，这对于自噬体的形成至关重要，并降低了 P62 的水平，提示在没有或存在 PA 的情况下增强了自噬流。该结果进一步通过感染 LC3-mRFP-GFP 慢病毒和 BafA1 阻断自噬体-溶酶体融合的方法得到证实。此外，gCTRP9 恢复了线粒体膜电位的丧失，抑制了 ROS 的产生，并减少了 PA 诱导的心肌细胞死亡。然而，自噬相关 5（ATG5）siRNA 阻断自噬后，gCTRP9 对心脏脂肪毒性的保护作用部分被消除，表明 gCTRP9 对细胞存活的作用主要通过调节自噬来介导。
结论
gCTRP9 诱导的自噬可以作为一种治疗心肌细胞氧化应激损伤的潜在策略。
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