Inhibition of TLR4/MAPKs Pathway Contributes to the Protection of Salvianolic Acid A Against Lipotoxicity-Induced Myocardial Damage in Cardiomyocytes and Obese Mice

Abstract

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.

Alcohol Abstinence Rescues Hepatic Steatosis and Liver Injury via Improving Metabolic Reprogramming in Chronic Alcohol-Fed Mice

“…Hepatic lipid accumulation induced by chronic alcohol intake, which in turn leads to lipotoxicity and further hepatocyte death, is a critical pathological mechanism in ALD. Previous studies including ours have indicated that TLR4/MAPKs pathway was mechanistically involved in alcohol- and lipotoxicity-induced hepatotoxicity [( Shen et al, 2018 ; Li et al, 2020 ; Yang et al, 2021 )]. Here, we evaluated the beneficial effect of abstinence on TLR4/MAPKs pathway.…”

Quercetin and Its Derivative Counteract Palmitate-Dependent Lipotoxicity by Inhibiting Oxidative Stress and Inflammation in Cardiomyocytes

“…Several literature reports suggest that PA induces myocardial damage that leads to cell death and cardiac dysfunction, thus providing an important method for inducing cardiac lipotoxicity in in vitro systems [ 52 , 53 , 54 ]. Accordingly, in this study, we first found that PA decreases cell viability and induces cell death in a dose-dependent manner (from 200 µM), indicating that an in vitro model of cytotoxicity induced by lipid overload has been successfully established.…”

Cimifugin Ameliorates Lipotoxicity-Induced Hepatocyte Damage and Steatosis through TLR4/p38 MAPK- and SIRT1-Involved Pathways

“…Lipotoxicity originated from abnormal lipid metabolism played a seriously detrimental role in metabolic diseases, including fatty liver diseases, obesity, cardiovascular diseases, and diabetes. Several lines of evidence indicated that alleviating lipotoxicity was an effective strategy for preventing or improving multiple metabolic diseases [ 31 , 32 ]. However, no medication targeting lipotoxicity has been proved in clinics.…”