Tetramethylpyrazine (TMP) switches energy signalling from the PKCζ-GLUT4-glucose pathway back to the SIRT1-CD36-fatty acid pathway similar to resveratrol to ameliorate cardiac myocyte lipotoxicity

Abstract

A B S T R A C TFatty acids and glucose are the main energy sources for the heart. Energy metabolic imbalance can cause many heart dysfunctions. Cardiomyocytes can switch to using fatty acids or glucose as an energy source. Palmitic acid (PA) treatment induces lipoptoxity and loss of mitochondrial function. We utilised PA treatment to simulate hyperlipidaemia and subsequently investigated the protective effects of tetramethylpyrazine (TMP) on the PAinduced cluster of differentiation 36 (CD36) and glucose transporter type 4 (GLUT4) signalling switch.The results showed that TMP can protect H9c2 cells and neonatal rat cardiomyocytes from PA-induced lipotoxicity similar to resveratrol significantly activated sirtuin1 to increase CD36 and decrease GLUT4 pathway proteins following treatment with PA, and switch the energy signalling GLUT4 pathway back to the CD36 pathway to ameliorate cardiac myocyte lipotoxicity and rescue the impaired energy metabolism. Therefore, we recommend TMP as a more efficient herbal component for maintaining the energy metabolism of the heart. ResveratrolEnergy metabolism impaired pathways Cardiomyoblast lipotoxicity

Fatty acid metabolism disorders and potential therapeutic traditional Chinese medicines in cardiovascular diseases

“…Furthermore, it was also found that Astragaloside IV could mitigate myocardial lipotoxic injury induced by abnormal lipid metabolism in DCM rats by reducing circulating TC, TG, and high‐density lipoprotein (HDL) levels and cardiac lipid accumulation (Wang et al, 2020). Similarly, tetramethylpyrazine, a biologically active ingredient extracted from Chuanxiong rhizoma, has been proved to inhibit palmitic acid‐induced lipotoxicity in H9C2 cells by increasing the expression of genes related to fatty acid metabolism, such as p‐AKT, p‐AMPK, SIRT1, PGC‐1α, PPAR‐α, CD36, and CPT‐1b (Chen, Li, et al, 2015; Chen, Tsai, et al, 2015). Broadly speaking, most traditional Chinese medicines ameliorate DCM by inhibiting fatty acid uptake while accelerating fatty acid oxidation.…”

“…Similarly, another study revealed that QiShenYiQi pills (QSYQ) had a protective effect in rats with cardiac hypertrophy. The underlying mechanism was associated with the activation of CPT‐1a‐mediated fatty acid metabolism (Chen, Li, et al, 2015; Chen, Tsai, et al, 2015). Huanglian Jiedu decoction (HLJDD) constituted with Coptidis rhizome (Huanglian), Scutellariae radix (Huangqin), Phellodendri chinensis cortex (Huangbai), and Gardeniae fructus (Zhizi), has been used for a long history in China.…”

“…The underlying mechanism was associated with the activation of CPT-1a-mediated fatty acid metabolism (Chen, Li, et al, 2015;Chen, Tsai, et al, 2015). Huanglian Jiedu decoction (HLJDD) constituted with…”