The MicroRNA-210/Casp8ap2 Pathway Alleviates Hypoxia-Induced Injury in Myocardial Cells by Regulating Apoptosis and Autophagy

Aim: This study was conducted to investigate the role of the miR-210/Caspase8ap2 pathway in apoptosis and autophagy in hypoxic myocardial cells. Methods: The miR-control, miR-210 mimic, and miR-210 inhibitor were transfected into rat myocardial H9C2 cells. The transfection efficiency of exogenous miR-210 was determined by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). H9C2 cells were then treated with CoCl2 for 24, 48, and 72 h to generate a myocardial injury model. The apoptosis of H9C2 cells was assessed by flow cytometry. Additionally, a western blot assay was used to determine the expression of the autophagy-associated proteins light chain 3 (LC3), p62 and Beclin-1, and apoptosis-associated proteins Caspase8ap2, cleaved caspase 8, and cleaved caspase 3. Results: We determined that a 48 h hypoxia treatment duration in H9C2 cardiomyocytes induced myocardial injury. Additionally, the overexpression of miR-210 significantly inhibited cell apoptosis. MiR-210 suppressed autophagy by upregulating p62 and downregulating LC3II/I in hypoxic H9C2 cells. Caspase8ap2 was a putative target of miR-210, miR-210 mediated apoptosis, and autophagy of H9C2 cells via suppressing Caspase8ap2. Furthermore, the expression of caspase 8, caspase 3, and Beclin-1 were decreased in response to miR-210. Conclusion: miR-210 exhibits anti-apoptosis and anti-autophagy effects, which alleviate myocardial injury in response to hypoxia.

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Ergosterol Attenuates LPS-Induced Myocardial Injury by Modulating Oxidative Stress and Apoptosis in Rats

Cellular Physiology and Biochemistry ◽

10.1159/000491887 ◽

2018 ◽

Vol 48 (2) ◽

pp. 583-592 ◽

Cited By ~ 11

Author(s):

Jianjun Xu ◽

Cai Lin ◽

Tingting Wang ◽

Peng Zhang ◽

Zhengjun Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Cytochrome C ◽

Myocardial Injury ◽

Caspase 3 ◽

Enzyme Linked Immunosorbent Assay ◽

H9c2 Cells ◽

Sod Activity ◽

Creatine Kinase Mb ◽

Associated Proteins ◽

Antioxidant Proteins

Background/Aims: Ergosterol (ER) is the primary sterol found in fungi and is named after the ergot fungus. A variety of pharmacological activities have been reported for ER, including antioxidative, anti-proliferative, and anti-inflammatory effects, although its role in sepsis remains unclear. Methods: The protective effect of ER on lipopolysaccharide (LPS)-induced sepsis myocardial injury was evaluated both in vivo and in vitro. Rats were pretreated with ER and then with LPS. Histopathology of heart tissues was first performed. Subsequently, the levels of superoxide dismutase (SOD), malondialdehyde (MDA), creatine kinase MB fraction (CK-MB), and lactate dehydrogenase (LDH) in serum and heart tissues were assessed by enzyme-linked immunosorbent assay kits. Western blotting was further used to evaluate the expression of antioxidant proteins (HO-1 and cytochrome c) and apoptosis associated proteins (Bcl-2, Bax, cleaved-caspase-3, cleaved-caspase-9, and cleaved-PARP). In addition, the effects of ER on oxidative stress biomarkers and apoptosis proteins were also detected in LPS-treated H9C2 cells. Moreover, small interfering Nrf2 RNA was transfected to H9C2 cells to study the role of Nrf2 signaling in connection with the protective effects of ER. Results: Pretreatment with ER ameliorated the histopathological changes in heart tissue induced by LPS injection, increased SOD activity, and reduced MDA content, and CK-MB and LDH levels. Furthermore, ER restored the expression of Nrf-2 and HO-1 in rat hearts, attenuating apoptotic damage via up-regulation of Bcl-2 in combination with the inhibition of Bax, cytochrome c, cleaved-caspase-3 and 9, and PARP, as revealed by western blot. When Nrf2 was blocked by siRNA, the effects of ER on SOD and MDA activity, as well as the expression of the antioxidant proteins and apoptosis-associated proteins were abolished. Conclusions: We demonstrated that ER has a cardioprotective effect in LPS-induced sepsis model through modulation of the antioxidant activity and anti-apoptosis effects and this process might be regulated by Nrf2 signaling.

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Nitric Oxide Alleviated High Salt–Induced Cardiomyocyte Apoptosis and Autophagy Independent of Blood Pressure in Rats

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.646575 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yong Li ◽

Xiaoguang Wu ◽

Yukang Mao ◽

Chi Liu ◽

Yiting Wu ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Caspase 3 ◽

High Salt ◽

Beclin 1 ◽

Cardiomyocyte Apoptosis ◽

Neonatal Rat ◽

Caspase 8 ◽

H9c2 Cells ◽

Cardiac Damage

The present study aimed to explore whether high-salt diet (HSD) could cause cardiac damage independent of blood pressure, and whether nitric oxide (NO) could alleviate high-salt–induced cardiomyocyte apoptosis and autophagy in rats. The rats received 8% HSD in vivo. H9C2 cells or primary neonatal rat cardiomyocytes (NRCM) were treated with sodium chloride (NaCl) in vitro. The levels of cleaved-caspase 3/caspase 3, cleaved-caspase 8/caspase 8, Bax/Bcl2, LC3 II/LC3 I, Beclin-1 and autophagy related 7 (ATG7) were increased in the heart of HSD rats with hypertension (HTN), and in hypertension-prone (HP) and hypertension-resistant (HR) rats. Middle and high doses (50 and 100 mM) of NaCl increased the level of cleaved-caspase 3/caspase 3, cleaved-caspase 8/caspase 8, Bax/Bcl2, LC3 II/LC3 I, Beclin-1, and ATG7 in H9C2 cells and NRCM. The endothelial NO synthase (eNOS) level was increased, but p-eNOS level was reduced in the heart of HSD rats and H9C2 cells treated with 100 mM NaCl. The level of NO was reduced in the serum and heart of HSD rats. NO donor sodium nitroprusside (SNP) reversed the increases of cleaved-caspase 3/caspase 3, cleaved-caspase 8/caspase 8, Bax/Bcl2 induced by NaCl (100 mM) in H9C2 cells and NRCM. SNP treatment attenuated the increases of cleaved-caspase 3/caspase 3, Bax/Bcl2, LC3 II/LC3 I, Beclin-1, and ATG7 in the heart, but had no effect on the blood pressure of HSD rats with HR. These results demonstrated that HSD enhanced cardiac damage independently of blood pressure. Exogenous NO supplementarity could alleviate the high salt–induced apoptosis and autophagy in cardiomyocytes.

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Quercetin attenuates lipopolysaccharide-induced myocardial cell apoptosis via modulation of cAMP-Epac pathway

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v18i9.4 ◽

2021 ◽

Vol 18 (9) ◽

pp. 1811-1815

Author(s):

YuHui Wang ◽

Qian Fu ◽

Baning Ye ◽

Yanpei Liu

Keyword(s):

Myocardial Injury ◽

Myocardial Cell ◽

H9c2 Cells ◽

Myocardial Cells ◽

Promising Strategy ◽

Associated Proteins ◽

Induced Apoptosis ◽

Interfering Rna ◽

Quercetin Treatment

Purpose: To investigate the effects and mechanism of action of quercetin (QUE) on sepsis-induced apoptosis of myocardial cells in vitro. Methods: Lipopolysaccharide (LPS) was used to induce apoptosis H9c2 myocardial cells. Apoptosis of H9c2 cells was determined by propidium iodide staining. Knock down of Epac1 was achieved using small interfering RNA (SiEpac1). The levels of associated proteins (Epac1 and Rap1) were evaluated by western blotting. Results: Lipopolysaccharide promoted apoptosis of H9c2 cells and inhibited the activity of cAMP-Epac pathway (p < 0.001 vs. control). Quercetin inhibited caspase 3 activity and apoptosis (p < 0.05 vs. LPS) induced by LPS via activation of cAMP-Epac1 signaling pathway. Moreover, Epac1 knockdown decreased the anti-apoptosis effect of Que, which indicates that Que attenuated apoptosis partly via cAMP-Epac pathway. Conclusion: Que attenuated LPS-induced apoptosis in myocardial cells via activation of cAMP-Epac1 pathway. Therefore, quercetin treatment may serve as a promising strategy in the treatment of sepsisinduced myocardial injury.

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Knockdown of BAG3 synergizes with olaparib to kill ovarian cancer cells via repressing autophagy

Journal of Investigative Medicine ◽

10.1136/jim-2020-001602 ◽

2020 ◽

pp. jim-2020-001602

Author(s):

Kexin Wang ◽

Jianhua Zheng

Keyword(s):

Ovarian Cancer ◽

Western Blot ◽

Transfection Efficiency ◽

Parp Inhibitor ◽

Beclin 1 ◽

Cell Counting ◽

Ovarian Cancer Cells ◽

Western Blot Assay ◽

Related Proteins

This study aimed at expounding the synergistic effect of Bcl-2-associated athanogene 3 (BAG3) knockdown and poly ADP-ribose polymerase (PARP) inhibitor on ovarian cancer (OC) cells and the potential mechanism. Short hairpin RNA (shRNA) targeting BAG3 (sh-BAG3) was transfected into SK-OV-3 (SKOV-3 ;SKOV3) and A2780 cells, and western blot assay was used to detect transfection efficiency. Cell proliferation and apoptosis were detected by the cell counting kit-8 method, 5-Bromodeoxyuridine (BrdU) experiment and flow cytometry analysis, respectively. The expressions of apoptosis-related proteins Bax and Bcl-2, as well as the expressions of autophagy-related proteins LC3-I, LC3-II and Beclin-1, were examined by western blot assay. Additionally, the cells were treated with autophagy activator rapamycin to investigate whether the tumor-suppressive function of BAG3 knockdown+PARP inhibitor was dependent on autophagy. In this work, we demonstrated that BAG3 knockdown further sensitized OC cells to olaparib treatment, reducing cellular viability and promoting apoptosis. Both sh-BAG3 and olaparib decreased the expression of Beclin-1 and the LC3-Ⅱ:LC3-I ratio, and their synergism further inhibited the process of autophagy. However, the aforementionede effects were reversed after the cells were treated with rapamycin. Based on these results, we concluded that BAG3 knockdown synergizes with olaparib to kill OC cells in vitro by repressing autophagy.

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Lipid emulsion attenuates apoptosis induced by a toxic dose of bupivacaine in H9c2 rat cardiomyoblast cells

Human & Experimental Toxicology ◽

10.1177/0960327115608930 ◽

2016 ◽

Vol 35 (9) ◽

pp. 929-937 ◽

Cited By ~ 8

Author(s):

S-H Ok ◽

J Yu ◽

Y Lee ◽

H Cho ◽

I-W Shin ◽

...

Keyword(s):

Cell Viability ◽

Lipid Emulsion ◽

Caspase 3 ◽

In Vitro Study ◽

Terminal Deoxynucleotidyl Transferase ◽

Caspase 8 ◽

Lipid Solubility ◽

H9c2 Cells ◽

Toxic Dose

The goal of this in vitro study was to investigate the effect of lipid emulsion on apoptosis induced by a toxic dose of bupivacaine (BPV) in H9c2 rat cardiomyoblast cell lines. The effect of lipid emulsion on the decreased cell viability and count induced by BPV or mepivacaine (MPV) in the H9c2 cells was assessed using an 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay or a cell count assay. The effect of BPV or lipid emulsion combined with BPV on cleaved caspase 3, caspase 8, and Bax in H9c2 cells was investigated using Western blotting. A terminal deoxynucleotidyl transferase dUTP2′-deoxyuridine 5′-triphosphate nick end-labeling (TUNEL) assay was performed to detect apoptosis of H9c2 cells treated with BPV alone or lipid emulsion combined with BPV. The magnitude of lipid emulsion-mediated attenuation of decreased cell viability induced by BPV was higher than that of lipid emulsion-mediated attenuation of decreased cell viability induced by MPV. Lipid emulsion attenuated the increases in cleaved caspase 3, caspase 8 and Bax induced by BPV. Lipid emulsion attenuated the increases in TUNEL-positive cells induced by BPV. These results suggest that lipid emulsion attenuates a toxic dose of BPV-induced apoptosis via inhibition of the extrinsic and intrinsic apoptotic pathways. The protective effect of lipid emulsion may be partially associated with the relatively high lipid solubility of BPV.

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Coupling Activation of Pro-Apoptotic Caspases With Autophagy in the Meckel´s Cartilage

Physiological Research ◽

10.33549/physiolres.933947 ◽

2018 ◽

pp. 135-140 ◽

Cited By ~ 1

Author(s):

P. Bíliková ◽

E. Švandová ◽

B. Veselá ◽

J. Doubek ◽

A. Poliard ◽

...

Keyword(s):

Caspase 3 ◽

Beclin 1 ◽

Hypertrophic Chondrocytes ◽

Caspase 8 ◽

Major Mechanism ◽

Histological Sections ◽

Temporary Structure ◽

Caspase 2 ◽

First Time

Mammalian Meckel´s cartilage is a temporary structure associated with mandible development. Notably, its elimination is not executed by apoptosis, and autophagy was suggested as the major mechanism. Simultaneous reports point to pro-apoptotic caspases as novel participants in autophagic pathways in general. The aim of this research was to find out whether activation of pro-apoptotic caspases (-2, -3, -6, -7, -8 and -9) was associated with autophagy of the Meckel´s cartilage chondrocytes. Active caspases were examined in serial histological sections of mouse mandible using immunodetection and were correlated with incidence of autophagy based on Beclin-1 expression. Caspase-2 and caspase-8 were found in Beclin-1 positive regions, whereas caspase-3, -6, -7 and -9 were not present. Caspase-8 was further correlated with Fas/FasL and HIF-1alpha, potential triggers for its activation. Some Fas and FasL positivity was observed in the chondrocytes but caspase-8 activation was found also in FasL deficient cartilage. HIF-1alpha was abundantly present in the hypertrophic chondrocytes. Taken together, caspase-8 activation in the Meckel´s cartilage was demonstrated for the first time. Caspase-8 and caspase-2 were the only pro-apoptotic caspases detected in the Beclin-1 positive segment of the cartilage. Activation of caspase-8 appears FasL/Fas independent but may be switched on by HIF-1alpha.

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Energy Metabolism Mechanism of Anticardiogenic Shock Effect Component Ginsenoside Rc of Shenfu Injection on H9c2 Myocardial Injury Cells Induced by Hypoxia/Reoxygenation

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/1828629 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yu Chen ◽

Yan Li ◽

Guoliang Xu ◽

Guangbin Shang ◽

Hongning Liu ◽

...

Keyword(s):

Energy Metabolism ◽

Cardiogenic Shock ◽

Myocardial Injury ◽

Time Effect ◽

Dose Effect ◽

Myocardial Cells ◽

Atp Content ◽

Shenfu Injection ◽

H9c2 Cardiomyocytes ◽

Ginsenoside Rc

Shenfu Injection (SFI) is a common drug used to treat cardiovascular diseases and has a significant effect on cardiogenic shock. Ginsenoside Rc (G-Rc) was an anticardiogenic shock effect component of SFI screened by UHPLC-Q-TOF/MS and multivariate statistical analysis and further selected by molecular docking experiment in our previous study. However, most studies on SFI in the treatment of cardiogenic shock focus on the overall efficacy, and little is known about its effective component on energy metabolism in hypoxia/reoxygenation- (H/R-) induced myocardial injury cells. Therefore, the present study was performed to investigate the dose-effect and time-effect relationship of G-Rc in protecting hypoxic injury of H9c2 cardiomyocytes, and its mechanism on the energy metabolism-related indicators, i.e., adenosine triphosphate (ATP) content, lactate dehydrogenase (LDH) release, and creatine kinase (CK) activity of the myocardial cells, was explored. In this paper, a stable and reliable H/R model of H9c2 cardiomyocytes was established. Compared with the control group, the activity of cardiomyocytes in the H/R group was significantly reduced (P<0.01). The dose-effect and time-effect studies showed that G-Rc could significantly increase cell viability at certain point compared with the H/R group (P<0.01), and the optimum intervention dose and time was 3.33 μmol/L for 12 h. The results concerning energy metabolism mechanism demonstrated that G-Rc pretreatment could improve ATP content, attenuate the LDH leakage, and decrease CK activity and apoptosis rate of H/R cardiomyocytes. Taken together, our findings suggest that G-Rc pretreatment can significantly protect myocardial cells from H/R injury. In addition, G-Rc is able to improve the energy metabolism ability of the injury cardiomyocytes by direct synthesis of ATP and reducing the activity of LDH, CK, and apoptosis rate. These results indicate that G-Rc may be a promising therapeutic candidate for the treatment of cardiovascular disease caused by myocardial H/R injury.

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Effect of polysaccharide from the root of Bupleurum Chinese DC and Bupleurum scorzonerifolium Willd on hydrogen peroxide-induced myocardial apoptosis

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i2.11 ◽

2020 ◽

Vol 19 (2) ◽

pp. 291-297

Author(s):

Jun-hui Gong ◽

Xue-qing Liu ◽

Wei-li Ouyang ◽

Hong-tao Zhu ◽

Xiao-jun Ding ◽

...

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Cell Viability ◽

Caspase 3 ◽

Raw Material ◽

Caspase 8 ◽

H9c2 Cells ◽

Caspase 9 ◽

Bupleurum Scorzonerifolium Willd ◽

Bupleurum Scorzonerifolium

Purpose: To investigate the protective effect of polysaccharide (BRP) from the root of Bupleurum Chinese DC. and Bupleurum scorzonerifolium Willd. on cardiomyocyte cells. Methods: Response surface methodology (RSM) based on Box-Behnken Design (BBD) was performed to optimize the extraction conditions for BRP. The effect of BRP on cardiomyocyte cell apoptosis was evaluated in H9c2 cells treated with hydrogen peroxide (H2O2). Cell viability was determined by CCK-8 assay, while oxidative stress levels in H9c2 cells, including lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT) and creatine kinase (CK) were determined using commercial kits following the manufacture’s instruction. mRNA expressions (caspase-3, caspase-8, caspase-9 and Fas) were determined by quantitative real time-polymerase chain reaction (RT-qPCR). Results: The obtained optimal extraction conditions for BRP was as follows: extraction time (1.43 h), ratio of water to the raw material (30 mL/g) and extraction times (2 times). BRP (200, 400, 600 and 800 μg/mL) significantly increased the cell viability of H2O2 induced H9c2 cells (p < 0.05, p < 0.01, p < 0.01, p < 0.01, respectively). BRP (200, 400 and 800 μg/mL) significantly decreased LDH and CK levels (p < 0.01, p < 0.01, p < 0.01, respectively). However, BRP increased levels of SOD (200, 400 and 800 μg/mL, p < 0.05) and CAT (400 and 800 μg/mL, p < 0.05) in H9c2 cells. BRP significantly downregulated mRNA expressions of Caspase-3, Caspase-8, Caspase-9 and Fas (200, 400 and 800 μg/mL, p < 0.01) in H9c2 cells induced by H2O2. Conclusion: BRP protects cardiomyocyte against apoptosis via inhibition of oxidative stress and mitochondria-mediated intrinsic apoptosis, and thus, may be potential therapeutic agent for the management of cardiovascular diseases. Keywords: Bupleurum Chinese, Bupleurum scorzonerifolium Willd., Polysaccharide, Cardiomyocyte, Apoptosis, H9c2 cell, Biochemical parameters

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Luteolin Induces Apoptosis and Autophagy in Mouse Macrophage ANA-1 Cells via the Bcl-2 Pathway

Journal of Immunology Research ◽

10.1155/2018/4623919 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Yuexia Liao ◽

Yang Xu ◽

Mengyao Cao ◽

Yuanyuan Huan ◽

Lei Zhu ◽

...

Keyword(s):

Caspase 3 ◽

Inflammatory Diseases ◽

Flow Cytometric Analysis ◽

Beclin 1 ◽

Caspase 8 ◽

Mouse Macrophage ◽

Expression Levels ◽

Traditional Medicines ◽

Flow Cytometric ◽

Induced Apoptosis

Plants rich in luteolin have been used as Chinese traditional medicines for inflammatory diseases, hypertension, and cancer. However, little is known about the effect of luteolin on the apoptosis or autophagy of the macrophages. In this study, mouse macrophage ANA-1 cells were incubated with different concentrations of luteolin. The viability of the cells was determined by an MTT assay, apoptosis was determined by flow cytometric analysis, the level of cell autophagy was observed by confocal microscopy, and the expression levels of apoptotic or autophagic and antiapoptotic or antiautophagic proteins were detected by Western blot analysis. The results showed that luteolin decreased the viability of ANA-1 cells and induced apoptosis and autophagy. Luteolin induced apoptosis accompanied by downregulation of the expression of Bcl-2 and upregulation of the expression of caspase 3 and caspase 8. And luteolin increased FITC-LC3 punctate fluorescence accompanied by the increased expression levels of LC3-I, ATG7, and ATG12, while it suppressed the expression level of Beclin-1. Luteolin treatment resulted in obvious activation of the p38, JNK, and Akt signaling pathways, which is important in modulating apoptosis and autophagy. Thus, we concluded that luteolin induced the apoptosis and autophagy of ANA-1 cells most likely by regulating the p38, JNK, and Akt pathways, inhibiting the activity of Bcl-2 and Beclin-1 and upregulating caspase 3 and caspase 8 expression. These results provide novel insights into a therapeutic strategy to prevent and possibly treat macrophage-related diseases through luteolin-induced apoptosis and autophagy.

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Abstract 11972: Ivabradine Attenuates Hypoxia/Reoxygenation-Induced Excessive Autophagy in H9c2 Cardiomyocyte by Modulation of the PI3K/Akt/mTOR Pathway

Circulation ◽

10.1161/circ.144.suppl_2.11972 ◽

2021 ◽

Vol 144 (Suppl_2) ◽

Author(s):

min yang ◽

Hui Li ◽

Wu Jiatian ◽

Hua Tianfeng

Keyword(s):

Cell Viability ◽

Kinase Inhibitor ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Mtor Pathway ◽

Beclin 1 ◽

Western Blot Assay ◽

Transmission Electron ◽

H9c2 Cardiomyocytes ◽

Hypoxia Reoxygenation

Introduction: Despite recent advances in resuscitation techniques, the mortality associated with survival from cardiac arrest (CA) still remains low. Cardiovascular ischemia/reperfusion injury (IRI) is one of the primary pathophysiology involved. Hypothesis: We assessed the hypothesis that ivabradine could attenuate hypoxia/reoxygenation injury of H9c2 cardiomyocytes by inhibiting excessive autophagy through PI3K/Akt/mTOR Pathway. Methods: Cultured H9c2 were randomly divided into 3 groups: CON (normoxia), H/R (hypoxia reoxygenation) and IVA. The IVA was divided into 4 subgroups, in which H9c2 were treated with or without ivabradine(20μM or 100μM) or PI3-kinase inhibitor LY294002(10μM) for 12 hours and then subjected to 12 hours of hypoxia and 24 hours of reoxygenation. Hypoxia was achieved by a hypoxia chamber filled with 5%CO 2 and 95% N 2 at 37°C. Cell viability were measured with CCK-8 assay kits. Cell autophagy was assessed by transmission electron microscopy (TEM). The expressions of autophagy marker protein (LC3, Beclin-1), PI3K, Akt and mTOR were determined by Western-blot assay. Results: A decrease of cell viability and an increase formulation of autophagosomes /autophagy lysozymes occurred after H/R. Significant improvement was noted in cells treated with ivabradine compared to H/R(Figure 1). Ivabradine promoted pmTOR/mTOR expression and lower expressions of LC3II/LC3I and Beclin 1. LY294002 antagonized the effects of ivabradine on antophagy (Figure 2). Conclusions: Ivabradine could protect H9c2 against H/R injury via inhibiting excessive autophagy through PI3K/Akt/mTOR pathway.

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