Qi-Li-Qiang-Xin Alleviates Isoproterenol-Induced Myocardial Injury by Inhibiting Excessive Autophagy via Activating AKT/mTOR Pathway

Abstract

Background: Apoptosis and autophagy are two important patterns of cell death in the process of heart failure. Qi-Li-Qiang-Xin (QLQX), a traditional Chinese medicine, has been frequently used in the treatment of chronic heart failure (CHF) in China. However, the potential effect of QLQX on autophagy has not been reported. In this study, we aimed to investigate whether QLQX alleviated isoproterenol (ISO)-induced myocardial injury through regulating autophagy. Methods: The rapid identification of chemical ingredients of QLQX was performed by UPLC-Q-TOF-MS, and the contents of major constituents in QLQX were also measured by UPLC-Q-TOF-MS. ISO was used to induce myocardial injury in H9c2 cardiomyocytes and SD rats. In vivo, cardiac function was evaluated by echocardiography and cardiac structure was observed by HE and Masson staining. Expressions of Bcl-2, Bax, LC3, P62, AKT, p-AKT, mTOR, and p-mTOR were detected by western blotting. In vitro, H9c2 cells were pretreated with QLQX for 3 h before ISO (80 µM, 48h) addressed. Cell viability, LDH and CK-MB release, apoptosis ratio, and the level of autophagy were measured. Western blotting was also performed to detected related protein expressions. Result: In vivo, treatment by QLQX significantly improved cardiac function and alleviated ISO-induced myocardial structural damage. In addition, QLQX markedly decreased apoptosis and inhibited autophagic activity, accompanied by activating the AKT/mTOR pathway. In vitro, the increased cell apoptosis induced by ISO was paralleling with the gradually increasing level of autophagy. Furthermore, 3-MA, an autophagic inhibitor, could block ISO-induced autophagy in H9c2 cells. Our results suggested that both QLQX and 3-MA treatment could decrease cell death induced by ISO, implying that QLQX protected against ISO-induced myocardial injury possibly by inhibiting excessive autophagy-mediated cell death. In addition, blockage of AKT signaling by an AKT inhibitor, capivasertib, could reduce the effect of QLQX on inhibiting ISO-induced apoptosis and autophagy-mediated cell death. Conclusion: QLQX could alleviate ISO-induced myocardial injury by inhibiting apoptosis and excessive autophagy-mediated cell death via activating the AKT/mTOR pathway.

Trimetazidine Ameliorates Myocardial Metabolic Remodeling in Isoproterenol-Induced Rats Through Regulating Ketone Body Metabolism via Activating AMPK and PPAR α

“…These changes verified the HF model in rats. Besides, heart rate and blood pressure were decreased while the plasma levels of BNP were significantly increased after ISO intervention (Wang et al, 2018;Fan et al, 2019). These results concur with previous studies.…”

“…The changes in rat associated with ISO-induced HF are similar to the pathological changes of myocardial tissue in the process of human heart failure. Hence ISO-induced HF in rats is an extensively applied model in experimental medical research (Fan et al, 2019). The heart failure model in our study was induced by subcutaneous injection with ISO.…”

“…ISO is a beta-adrenergic receptor agonist that could inhibit both β1 and β2. ISO is usually used to induce pathologic myocardial diseases experimentally ( Fan et al, 2019 ). ISO can bring about myocardial ischemia, further resulting in a particular form of metabolic and ultrastructural variations that induce irreversible injury.…”

Protective Effect of Geraniol on Oxidative, Inflammatory and Apoptotic Alterations in Isoproterenol-Induced Cardiotoxicity: Role of the Keap1/Nrf2/HO-1 and PI3K/Akt/mTOR Pathways

“…These results indicate that geraniol caused the activation of PI3k/Akt in a dose-dependent manner and suggest that it may have modulated the myocardial autophagy by this mechanism. In previous studies, numerous drugs have demonstrated cardioprotective activity through activation of the PI3K/Akt pathway; examples include Paeonol and danshensu [ 5 ], Vasicine [ 26 ], Qi-Li-Qiang-Xin (a traditional Chinese medication) [ 28 ], and Levosimendan [ 29 ]. Activation of the PI3K/Akt/mTOR pathway also protected against myocardial injury by diminishing oxidative stress, limiting the inflammatory cascade, and deterring apoptosis in vivo and in vitro [ 8 ].…”

Qiliqiangxin Capsules Optimize Cardiac Metabolism Flexibility in Rats With Heart Failure After Myocardial Infarction

“…The high reproducibility of QLQX was clarified by a fingerprint analysis, which exhibited a high similarity of 10 batches ranging from 0.978 to 1.000 ( Zhang J. et al, 2013 ). Previous chemical analysis of QLQX, which was obtained from the same supplier and had the same batch number with QLQX in this study, identified the profile and concentrations of stable active ingredients ( Fan et al, 2019 ). Enalapril was obtained from Yangzijiang Pharmaceutical Group Jiangsu Pharmaceutical Co., Ltd. (Taizhou, Jiangsu, China) as the positive control.…”