Yang Zhen, Chen Yanli, Yan Zhaoyuan, Xu Tian Tian, Wu Xiangyao, Pi Aiwen, Liu Qingsheng, Chai Hui, Li Songtao, Dou Xiaobing
College of Basic Medicine and Public Health, Zhejiang Chinese Medical University, Hangzhou, China.
College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China.
Front Pharmacol. 2021 Mar 8;12:627123. doi: 10.3389/fphar.2021.627123. eCollection 2021.
The occurrence of lipotoxicity during obesity-associated cardiomyopathy is detrimental to health. Salvianolic acid A (SAA), a natural polyphenol extract of (Danshen in China), is known to be cardioprotective. However, its clinical benefits against obesity-associated cardiomyocyte injuries are unclear. This study aimed at evaluating the protective effects of SAA against lipotoxicity-induced myocardial injury and its underlying mechanisms in high fat diet (HFD)-fed mice and in palmitate-treated cardiomyocyte cells (H9c2). Our analysis of aspartate aminotransferase and creatine kinase isoenzyme-MB (CM-KB) levels revealed that SAA significantly reversed HFD-induced myocardium morphological changes and improved myocardial damage. Salvianolic acid A pretreatment ameliorated palmitic acid-induced myocardial cell death and was accompanied by mitochondrial membrane potential and intracellular reactive oxygen species improvement. Analysis of the underlying mechanisms showed that SAA reversed myocardial TLR4 induction in HFD-fed mice and H9c2 cells. Palmitic acid-induced cell death was significantly reversed by CLI-95, a specific TLR4 inhibitor. TLR4 activation by LPS significantly suppressed SAA-mediated lipotoxicity protection. Additionally, SAA inhibited lipotoxicity-mediated expression of TLR4 target genes, including MyD88 and -JNK/MAPK in HFD-fed mice and H9c2 cells. However, SAA did not exert any effect on palmitic acid-induced SIRT1 suppression and -AMPK induction. In conclusion, our data shows that SAA protects against lipotoxicity-induced myocardial damage through a TLR4/MAPKs mediated mechanism.
肥胖相关性心肌病期间脂毒性的发生对健康有害。丹酚酸A（SAA）是中国丹参中的一种天然多酚提取物，已知具有心脏保护作用。然而，其对肥胖相关性心肌细胞损伤的临床益处尚不清楚。本研究旨在评估SAA对高脂饮食（HFD）喂养小鼠和棕榈酸处理的心肌细胞（H9c2）中脂毒性诱导的心肌损伤的保护作用及其潜在机制。我们对天冬氨酸转氨酶和肌酸激酶同工酶-MB（CM-KB）水平的分析表明，SAA显著逆转了HFD诱导的心肌形态学变化并改善了心肌损伤。丹酚酸A预处理改善了棕榈酸诱导的心肌细胞死亡，并伴随着线粒体膜电位和细胞内活性氧的改善。对潜在机制的分析表明，SAA逆转了HFD喂养小鼠和H9c2细胞中心肌TLR4的诱导。棕榈酸诱导的细胞死亡被特异性TLR4抑制剂CLI-95显著逆转。LPS激活TLR4显著抑制了SAA介导的脂毒性保护作用。此外，SAA抑制了脂毒性介导的TLR4靶基因的表达，包括HFD喂养小鼠和H9c2细胞中的MyD88和-JNK/MAPK基因。然而，SAA对棕榈酸诱导的SIRT1抑制和-AMPK诱导没有任何影响。总之，我们的数据表明，SAA通过TLR4/MAPKs介导的机制保护免受脂毒性诱导的心肌损伤。
