Exercise Training Protects Against Acute Myocardial Infarction via Improving Myocardial Energy Metabolism and Mitochondrial Biogenesis

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Background/Aims: A traditional Chinese medicine, Qiliqiangxin (QLQX) has been identified to perform protective effects on myocardium energy metabolism in mice with acute myocardial infarction, though the effects of QLQX on myocardial mitochondrial biogenesis under physiological condition is still largely elusive. Methods: H9C2 cells were treated with different concentrations of QLQX (0.25, 0.5, and 1.0 μg/mL) from 6 to 48 hours. Oxidative metabolism and glycolysis were measured by oxygen consumption and extracellular acidification with XF96 analyzer (SeaHorse). Mitochondrial content and ultrastructure were assessed by Mitotracker staining, confocal microscopy, flow cytometry, and transmission electron microscopy. Mitochondrial biogenesis-related genes were measured by qRT-PCR and Western blot. Results: H9C2 cells treated with QLQX exhibited increased glycolysis at earlier time points (6, 12, and 24 hours), while QLQX could enhance oxidative metabolism and mitochondrial uncoupling in H9C2 cells with longer duration of treatment (48 hours). QLQX also increased mitochondrial content and mitochondrial biogenesis-related gene expression levels, including 16sRNA, SSBP1, TWINKLE, TOP1MT and PLOG, with an activation of peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α) and its downstream effectors. Silencing PGC-1α could abolish the increased mitochondrial content in H9C2 cells treated with QLQX. Conclusion: Our study is the first to document enhanced metabolism in cardiomyocytes treated with QLQX, which is linked to increased mitochondrial content and mitochondrial biogenesis via activation of PGC-1α.S. Lin, X. Wu and L. Tao contributed equally to this work.

Section: Discussionmentioning

confidence: 99%

The Metabolic Effects of Traditional Chinese Medication Qiliqiangxin on H9C2 Cardiomyocytes

Lin¹,

Wu²,

Tao³

et al. 2015

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“…Notably, the mitochondria-dependent pathway plays a key role in I/R-induced myocardial cell apoptosis [3,4,10]. The most typical characteristic of myocardial ischemia is severe hypoxia, which could cause acidosis, energy depletion, and ion homeostasis rupture, ultimately resulting in cardiomyocyte death [11]. Mitochondria are abundant in myocardial cells and are responsible for energy metabolism by utilizing oxygen, and they are undoubtedly involved in the pathophysiological changes that occur during I/R injury.…”

Section: Introductionmentioning

confidence: 99%

Geniposide Prevents Hypoxia/Reoxygenation-Induced Apoptosis in H9c2 Cells: Improvement of Mitochondrial Dysfunction and Activation of GLP-1R and the PI3K/AKT Signaling Pathway

Jiang

Chang²,

Wang³

et al. 2016

105

Background/Aims: Myocardial ischemia/reperfusion injury is a major cause of morbidity and mortality associated with coronary heart disease. Many studies have demonstrated that natural products are promising chemotherapeutic drugs counteracting the loss of cardiomyocytes. Thus, the purpose of the present study was to investigate the effects of geniposide, a traditional Chinese herb extract from Gardenia jasminoides J. Ellis, on cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R) in H9c2 cells, and their underlying mechanisms. Methods: Cell viability and apoptosis ratio were assessed using the cell counting kit-8 assay and Annexin V/propidium iodide (PI) staining. The concentrations of lactate dehydrogenase (LDH), intracellular total superoxide dismutase (T-SOD), and malondialdehyde (MDA) were detected by microplate reader. The production of reactive oxygen species/reactive nitrogen species (ROS/RNS), the level of mitochondrial calcium, and mitochondrial membrane potential depolarization were measured by confocal laser scanning microscopy. Mitochondrial morphology was visualized using transmission electron microscopy. The expressions of Bcl-2 mRNA and Caspase-3 mRNA were measured by reverse transcription-polymerase chain reaction (RT-PCR). The protein levels of cleaved caspase-3, Bcl-2, Bax, AKT, p-AKT^serine473, cytochrome-c were detected by western bloting. Results: Geniposide pretreatment increased cell viability, decreased LDH levels in the supernatant, and inhibited cardiomyocyte apoptosis caused by H/R. Furthermore, geniposide reversed mitochondrial dysfunction by decreasing oxidative stress products (ROS/RNS and MDA), increasing anti-oxidative enzyme (T-SOD) level, improving mitochondrial morphology, attenuating mitochondrial calcium overload and blunting depolarization of mitochondrial membrane. Moreover, geniposide pretreatment increased Bcl-2 level and decreased Bax level, thus enhancing the Bcl-2/Bax ratio. Consistent with the above result, Bcl-2 mRNA expression was upregulated and caspase-3 mRNA expression was downregulated by geniposide. In addition, geniposide decreased the protein expression of cleaved caspase-3 and cytochrome-c and increased the level p-AKT^serine473. The protective effects of geniposide were partially reversed by glucagon-like pepitide-1 receptor antagonist exendin-(9-39) and the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002. Conclusions: Our results suggest that geniposide pretreatment inhibits H/R-induced myocardial apoptosis by reversing mitochondrial dysfunction, an effect in part due to activation of GLP-1R and PI3K/AKT signaling pathway.

“…Myocardial infarction causes mitochondria dysfunction or damage, thus hindering ATP production and leading to cell apoptosis [22,23]. It is important for cells to remove excessive damaged mitochondria through degradation such as autophagy [24].…”

Section: Introductionmentioning

confidence: 99%

Exogenous HGF Prevents Cardiomyocytes from Apoptosis after Hypoxia via Up-Regulating Cell Autophagy

Wang

Liu

Tao

et al. 2016

Background: Hepatocyte growth factor (HGF) is widely known as a protective factor in ischemic myocardium, however HGF sensitive cellular mechanism remained ill-defined. Autophagy at early stage of hypoxia has been demonstrated to play a role in protecting myocardium both in vivo and vitro. We performed this study to investigate the association between the protective effect of HGF and autophagy. Methods: Ventricular myocytes were isolated from neonatal rat heart (NRVMs). We evaluated cardiomyocytes apoptosis by Hoechst staining and flow cytometry. Autophagy was assessed by transmission electron microscope and mRFP-GFP-LC3 adenovirus infection. Mitochondrial membrane potential was estimated by JC-1 staining. Western blotting and ELISA assay were used to quantify protein concentrations. Results: We found that autophagy in NRVMs increased at early stage after hypoxia and HGF release was consistent with the change of autophagy. Exogenous HGF enhanced autophagy and decreased apoptosis, while neutralizing HGF yielded opposite effects. Besides, inhibition of autophagy increased apoptosis of myocytes. Furthermore, exogenous HGF induced Parkin, the marker of mitochondrial autophagy, indicating increased clearance of injured mitochondria. Conclusions: Our results revealed a potential mechanism in which exogenous HGF prevented NRVMs from apoptosis after hypoxia. Upregulation of Parkin through administration of exogenous HGF may be a potential therapeutic strategy ptotecting myocytes during ischemia.