Inhibition of TLR4/MAPKs Pathway Contributes to the Protection of Salvianolic Acid A Against Lipotoxicity-Induced Myocardial Damage in Cardiomyocytes and Obese Mice.
Inhibition of TLR4/MAPKs Pathway Contributes to the Protection of Salvianolic Acid A Against Lipotoxicity-Induced Myocardial Damage in Cardiomyocytes and Obese Mice.
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TLR4/MAPKs 通路的抑制有助于丹酚酸 A 保护心肌细胞和肥胖小鼠免受脂毒性诱导的心肌损伤
DOI：
10.3389/fphar.2021.627123
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发表时间：
2021
影响因子：
5.6
通讯作者：
Dou X
中科院分区：
文献类型：
--
作者：
Yang Z;Chen Y;Yan Z;Xu TT;Wu X;Pi A;Liu Q;Chai H;Li S;Dou X
肥胖相关性心肌病发生脂毒性对健康有害。丹参酸A（SAA）是丹参（中国丹参）的天然多酚提取物，具有心脏保护作用。然而，其对肥胖相关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）喂养小鼠和棕榈酸酯处理的心肌细胞（H9 c2）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，改善了心肌损伤。丹参酮A预处理可改善软脂酸诱导的心肌细胞死亡，并伴有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H9 c2细胞中心肌TLR 4的诱导。棕榈酸诱导的细胞死亡被一种特异性TLR 4抑制剂CLI-95显著逆转。LPS激活TLR 4可显著抑制SAA介导的脂毒性保护作用。此外，SAA抑制脂毒性介导的TLR 4靶基因的表达，包括HFD喂养的小鼠和H9 c2细胞中的MyD 88和p-JNK/MAPK。然而，SAA对棕榈酸诱导的SIRT 1抑制和p-AMPK诱导没有任何影响。总之，我们的数据表明，SAA通过TLR 4/MAPKs介导的机制保护脂毒性诱导的心肌损伤。
The occurrence of lipotoxicity during obesity-associated cardiomyopathy is detrimental to health. Salvianolic acid A (SAA), a natural polyphenol extract of Salvia miltiorrhiza Bunge (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 p-JNK/MAPK in HFD-fed mice and H9c2 cells. However, SAA did not exert any effect on palmitic acid-induced SIRT1 suppression and p-AMPK induction. In conclusion, our data shows that SAA protects against lipotoxicity-induced myocardial damage through a TLR4/MAPKs mediated mechanism.
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