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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.

SUBMITTER: Fan C

PROVIDER: S-EPMC6861302 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Fan Cailian C Tang Xiyang X Ye Mengnan M Zhu Guonian G Dai Yi Y Yao Zhihong Z Yao Xinsheng X

Frontiers in pharmacology 20191112

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 ident ...[more]

PMID: 31780944

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Project description:Cardiac dysfunction is a critical manifestation of sepsis-induced multiorgan failure and results in the high mortality of sepsis. Our previous study demonstrated that a traditional Chinese medicine formula, Qiang-Xin 1 (QX1), ameliorates cardiac tissue damage in septic mice; however, the underlying pharmacology mechanism remains to be elucidated. The present study was aimed at clarifying the protective mechanism of the QX1 formula on sepsis-induced cardiac dysfunction. The moderate sepsis model of mice was established by cecal ligation and puncture surgery. Treatment with the QX1 formula improved the 7-day survival outcome, attenuated cardiac dysfunction, and ameliorated the disruption of myocardial structure in septic mice. Subsequent systems pharmacology analysis found that 63 bioactive compounds and the related 79 candidate target proteins were screened from the QX1 formula. The network analysis showed that the QX1 active components quercetin, formononetin, kaempferol, taxifolin, cryptotanshinone, and tanshinone IIA had a good binding activity with screened targets. The integrating pathway analysis indicated the calcium, PI3K/AKT, MAPK, and Toll-like receptor signaling pathways may be involved in the protective effect of the QX1 formula on sepsis-induced cardiac dysfunction. Further, experimental validation showed that the QX1 formula inhibited the activity of calcium/calmodulin-dependent protein kinase II (CaMKII), MAPK (P38, ERK1/2, and JNK), and TLR4/NF-κB signaling pathways but promoted the activation of the PI3K/AKT pathway. A cytokine array found that the QX1 formula attenuated sepsis-induced upregulated levels of serum IFN-γ, IL-1β, IL-3, IL-6, IL-17, IL-4, IL-10, and TNF-α. Our data suggested that QX1 may represent a novel therapeutic strategy for sepsis by suppressing the activity of calcium, MAPK, and TLR4/NF-κB pathways, but promoting the activation of AKT, thus controlling cytokine storm and regulating immune balance. The present study demonstrated the multicomponent, multitarget, and multipathway characteristics of the QX1 formula and provided a novel understanding of the QX1 formula in the clinical application on cardiac dysfunction-related diseases.

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Project description:BackgroundCachexia has a devastating impact on survival and quality of life for many cancer patients and contributes to nearly one-third of all cancer deaths; also, it is associated with poor responses to chemotherapy and survival. A better understanding of the underlying mechanisms of cancer-associated cachexia (CAC), coupled with effective therapeutic approaches, will improve management of progressive functional impairment in cancer patients. Salidroside, a phenylpropanoid glycoside in Rhodiola rosea L, has been reported to possess potential anti-fatigue, anti-ageing, and anti-Alzheimer's disease properties. It is widely consumed as a nutritional supplement, but its effects on CAC and the possible mechanism remain a mystery.MethodsIn the murine models of cachexia induced by CT-26 and Lewis lung carcinoma (LLC) tumour, respectively, main features of CAC were determined after treatment of salidroside or chemotherapy. In vitro experiments were performed using murine C2C12 myotubes, which were treated by tumour necrosis factor-α. Levels of several critical muscle-related signal proteins such as mammalian target of rapamycin (mTOR), p-mTOR, and myosin heavy chain (MyHC) were examined using western blot both in vitro and in vivo.ResultsIn the present study, we showed the exciting effect of salidroside on the treatment of CAC. In CT-26 and LLC models, respectively, salidroside treatment could effectively preserve the tumour-free body weight, decrease loss of adipose and gastrocnemius muscles, alleviate tumour burden, and prolong their survival time. Additionally, in combined chemotherapy, salidroside could synergistically enhance the anti-tumour activity of cisplatin, especially decreased or eliminated chemotherapy-induced cachexia. Further analysis demonstrated that salidroside could significantly increase expression of mTOR, p-mTOR, and MyHC in gastrocnemius muscle. Also, results in vitro showed that salidroside could not only obviously increase mTOR, p-mTOR, and MyHC expression in C2C12 myotubes but also effectively rescue their down-regulation induced by tumour necrosis factor-α.ConclusionsIn the current study, the exciting effect of salidroside on CAC suggested that salidroside supplementation might be a promising approach for a multi-targeted therapy for the treatment of CAC.

Dataset Information

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

Publications

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

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