Abstract 22: Calpain-Dependent Induction of Endoplasmic Reticulum Stress in Cardiomyocyte Apoptosis and Post--Myocardial Infarction Remodeling

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Dong Zheng ◽  
Jian Ma ◽  
Meng Wei ◽  
Huaxi Xu ◽  
Tianqing Peng
Keyword(s):  
Myocardial Infarction ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Myocardial Injury ◽  
Cardiomyocyte Apoptosis ◽  
Post Myocardial Infarction ◽  
H9c2 Cells ◽  
Calpain Activity ◽  
Over Expression ◽  
Myocardial Remodelling

Background: Calpain is up-regulated and implicated in cardiomyocyte apoptosis and myocardial remodelling post myocardial infarction. Endoplasmic reticulum (ER) stress is induced and contributes to myocardial injury in a variety of cardiac diseases. This study was to investigate whether calpain plays a role in ER stress, thereby mediating apoptosis in cardiomyocytes and myocardial remodelling after infarction. Methods and Results: In rat cardiomyoblasts H9C2 cells, over-expression of calpain-1 increased the protein levels of Bip and CHOP, indicative of ER stress, and induced apoptosis determined by a decrease in Bcl-2 and increases in caspase-3 activation and DNA fragmentation. Inhibition of calpain activity or ER stress prevented apoptosis induced by calpain-1 over-expression. In contrast, over-expression of calpain-2 failed to induce apoptosis. The induction of ER stress by calpain-1 might be mediated through SERCA2a/Calcium signaling as up-regulation of calpain-1 reduced SERCA2a protein and elevated intracellular free Calcium in H9C2 cells. In a mouse model of myocardial infarction induced by coronary artery ligation, calpain activity was increased and ER stress was induced in the infracted heart. Up-regulation of calpastatin, the endogenous calpain inhibitor, inhibited calpain activation, prevented ER stress and apoptosis, reduced myocardial remodelling and improved myocardial function after infarction in calpastatin transgenic mice compared with their wild-type littermates. Conclusion: Calpain-1 induces ER stress through the proteolysis of SERCA2a, thereby mediating apoptosis in cardiomyocytes. Inhibition of calpain prevents ER stress and apoptosis, reduces myocardial remodelling and dysfunction after infarction. Thus, ER stress may represent a novel mechanism by which calpain mediates myocardial injury in the infracted heart.

scholarly journals Over-expression of calpastatin attenuates myocardial injury following myocardial infarction by inhibiting endoplasmic reticulum stress

2018 ◽  
Vol 10 (9) ◽  
pp. 5283-5297 ◽  
Author(s):  
Shuai Li ◽  
Jian Ma ◽  
Jing-Bo Li ◽  
James C. Lacefield ◽  
Douglas L. Jones ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Myocardial Injury ◽  
Over Expression

scholarly journals EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1198
Author(s):  
Juliana Gomez ◽  
Zammam Areeb ◽  
Sarah F. Stuart ◽  
Hong P. T. Nguyen ◽  
Lucia Paradiso ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Viability ◽  
Er Stress ◽  
Cell Survival ◽  
Glioblastoma Cells ◽  
Over Expression ◽  
Stress Markers ◽  
Apoptotic Protein ◽  
Novel Association ◽  
Reduced Activity

Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.

scholarly journals MicroRNA-486 Alleviates Hypoxia-Induced Damage in H9c2 Cells by Targeting NDRG2 to Inactivate JNK/C-Jun and NF-κB Signaling Pathways

2018 ◽  
Vol 48 (6) ◽  
pp. 2483-2492 ◽  
Author(s):  
Xinling Zhang ◽  
Chunxiang Zhang ◽  
Nan Wang ◽  
Yan Li ◽  
Debing Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Cell Viability ◽  
Signaling Pathways ◽  
Myocardial Injury ◽  
Cell Counting ◽  
Migration And Invasion ◽  
High Morbidity ◽  
H9c2 Cells ◽  
Myocardial Ischemia And Reperfusion

Background/Aims: Acute myocardial infarction is a serious disease with high morbidity and mortality. microRNAs (miRNAs) have been proved to play an important role in modulating myocardial ischemia and reperfusion injury. Hence, in this study, we constructed H9c2 cell model to elucidate the roles of microRNA-486 (miR-486) in preventing hypoxia-induced damage in H9c2 cells. Methods: H9c2 cells were cultured in hypoxic incubator with 1% O2 to simulate hypoxia and/or transfected with miR-486 mimic, scramble, anti-miR-486, si-N-myc downstream-regulated gene 2 (NDRG2) and their corresponding negative controls (NC). Effects of miR-486 and/or NDRG2 dysregulation on hypoxia-induced myocardial injury in H9c2 cells were investigated by evaluating cell viability, migration, invasion and apoptosis using Cell Counting Kit-8 (CCK-8), transwell assay, flow cytometry, respectively. The proteins expression and RNA expression were detected by western blot and quantitative real time polymerase chain reaction (qRT-PCR), respectively. Results: Hypoxia treatment induced damage in H9c2 cells by decreasing cell viability, migration and invasion and increasing cell apoptosis. Moreover, hypoxia inhibited the expression of miR-486 in H9c2 cells. Overexpression of miR-486 alleviated hypoxia-induced myocardial injury in H9c2 cells, while suppression of miR-486 further aggravated hypoxia-induced injury. Furthermore, NDRG2 expression was negatively regulated by miR-486, and NDRG2 was confirmed as a target of miR-486. Knockdown of NDRG2 alleviated the effects of miR-486 suppression on hypoxia-induced myocardial injury. Besides, knockdown of NDRG2 markedly inhibited the activation of c-Jun N-terminal kinase (JNK) /c-jun and nuclear factor κB (NF-κB) signaling pathways in hypoxia-induced H9c2 cells. Conclusion: Our findings indicate that miR-486 may alleviate hypoxia-induced myocardial injury possibly by targeting NDRG2 to inactivate JNK/c-jun and NF-κB signaling pathways. miR-486 may be a potential target for treating ischemic myocardial injury following acute myocardial infarction.

scholarly journals Down-modulation of endoplasmic reticulum stressinitiated apoptosis by huperzine A in isoproterenolprovoked myocardial infarction rat model: Role of Nrf2/HO- 1 signaling axis

2020 ◽  
Vol 19 (8) ◽  
pp. 1685-1691
Author(s):  
Zhongkui Li ◽  
Lufang Gao ◽  
Daokang Xiang ◽  
Wenbo Liu
Keyword(s):  
Myocardial Infarction ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Rat Model ◽  
B Cell Lymphoma ◽  
Huperzine A ◽  
Calcium Handling ◽  
Heme Oxygenase 1 ◽  
Caspase 12 ◽  
Stress Parameters

Purpose: To investigate the myocardial protective effect of huperzine A (HPA), a sesquiterpene alkaloid, in a rat model of isoproterenol (ISP)- provoked MI and ER stress.Methods: Three groups of rats were used: control, ISP and ISP+HPA groups. The following indices were assayed using standard protocols: oxidative stress parameters, including NADPH oxidase 4 (NOX4), reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1); indices of calcium homeostasis, namely, sarcoplasmic and endoplasmic reticulum calcium ATPase isoform 2a (SERCA2a); ER stress parameters, viz, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), glucose-regulated protein 78 (GRP78), and C/EBP homologous protein (CHOP); and indices of apoptosis, i.e., B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and caspase-12].Results: Oxidative/ER stress and cardiomyocyte apoptosis were up-modulated (p < 0.05), while SERCA2a, a key calcium handling channel, was downmodulated in the ISP group (p < 0.05). In contrast, HPA treatment ameliorated these ISP-induced myocardial aberrations. (p < 0.05).Conclusion: These results indicate that HPA might be a potential therapeutic candidate for MI and associated cardiac problems. Keywords: Caspase-12, ER stress, Huperzine A, Myocardial infarction, SERCA2a

scholarly journals Oxidative and endoplasmic reticulum stresses are involved in palmitic acid-induced H9c2 cell apoptosis

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Lei Yang ◽  
Gaopeng Guan ◽  
Lanjie Lei ◽  
Jianyun Liu ◽  
Lingling Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Palmitic Acid ◽  
Er Stress ◽  
Cell Apoptosis ◽  
H9c2 Cell ◽  
H9c2 Cells ◽  
Proliferation And Apoptosis ◽  
H9c2 Cardiomyocytes ◽  
Heart Muscle Cells

Abstract Palmitic acid (PA) is the most common saturated long-chain fatty acid that causes damage to heart muscle cells. However, the molecular mechanism of PA toxicity in myocardial cells is not fully understood. In the present study, we explored the effects of PA on proliferation and apoptosis of H9c2 cardiomyocytes, and uncovered the signaling pathways involved in PA toxicity. Our study revealed induction of both oxidative and endoplasmic reticulum (ER) stresses and exacerbation of apoptosis in PA-treated H9c2 cells. Inhibition of oxidative stress by N-acetylcysteine (NAC) reduced apoptosis and decreased ER stress in PA-treated H9c2 cells. Moreover, inhibition of ER stress by 4-phenyl butyric acid decreased apoptosis and attenuated oxidative stress. In summary, the present study demonstrated that oxidative stress coordinates with ER stress to play important roles in PA-induced H9c2 cell apoptosis.

SMYD1 alleviates septic myocardial injury by inhibiting endoplasmic reticulum stress

2021 ◽  
Author(s):  
Meixue Chen ◽  
Jing Li ◽  
Jinfeng Wang ◽  
Yuan Le ◽  
Chunfeng Liu
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Heart Development ◽  
Cell Injury ◽  
Cardiac Injury ◽  
Major Complication ◽  
Inflammatory Factors ◽  
H9c2 Cells ◽  
H9c2 Cardiomyocytes

Abstract Sepsis-induced cardiomyopathy (SIC) is a major complication of sepsis. SET and MYND domain containing 1 (SMYD1) has central importance in heart development, and its role in SIC has not been identified. Herein, we found that the expression of SMYD1 was downregulated in myocardial tissues of SIC patients (from GEO database: GSE79962) and lipopolysaccharide (LPS)-induced SIC rats, and LPS-induced H9c2 cardiomyocytes. We used LPS-stimulated H9c2 cells that mimic sepsis in vitro to explore the function of SMYD1 in SIC. MTT assay, LDH and CK-MB release assay, flow cytometry, and ELISA assay showed that SMYD1 overexpression enhanced cell viability, alleviated cell injury, impeded apoptosis, and reduced the level of pro-inflammatory factors and NF-κB activation under the condition of LPS stimulation. Moreover, SMYD1 exerted protective effect on H9c2 cells stimulated with LPS through relieving endoplasmic reticulum (ER) stress. In conclusion, overexpression of SMYD1 alleviates cardiac injury through relieving ER stress during sepsis.

scholarly journals Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress

2018 ◽  
Vol 46 (1) ◽  
pp. 9-22 ◽  
Author(s):  
Dong Huang ◽  
Mei-ling Yan ◽  
Kan-kai Chen ◽  
Rong Sun ◽  
Zhi-feng Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cardiorenal Syndrome ◽  
Protective Effects ◽  
Subtotal Nephrectomy ◽  
Silent Information Regulator 1 ◽  
Crs Model ◽  
Functional Deterioration ◽  
Morphologic Changes

Background/Aims: Increased endoplasmic reticulum (ER) stress contributes to development of cardiorenal syndrome (CRS), and Silent Information Regulator 1 (SIRT1), a class III histone deacetylase, may have protective effects on heart and renal disease, by reducing ER stress. We aimed to determine if SIRT1 alleviates CRS through ER stress reduction. Methods: Wild type mice (n=37), mice with cardiac-specific SIRT1 knockout (n=29), or overexpression (n=29), and corresponding controls, were randomized into four groups: sham MI (myocardial infarction) +sham STNx (subtotal nephrectomy); MI+sham STNx; sham MI+STNx; and MI+STNx. To establish the CRS model, subtotal nephrectomy (5/6 nephrectomy, SNTx) and myocardial infarction (MI) (induced by ligation of the left anterior descending (LAD) coronary artery) were performed successively to establish CRS model. At week 8, the mice were sacrificed after sequential echocardiographic and hemodynamic studies, and then pathology and Western-blot analysis were performed. Results: Neither MI nor STNx alone significantly influenced the other healthy organ. However, in MI groups, STNx led to more severe cardiac structural and functional deterioration, with increased remodeling, increased BNP levels, and decreased EF, Max +dp/dt, and Max -dp/dt values than in sham MI +STNx groups. Conversely, in STNx groups, MI led to renal structural and functional deterioration, with more severe morphologic changes, augmented desmin and decreased nephrin expression, and increased BUN, SCr and UCAR levels. In MI+STNx groups, SIRT1 knockout led to more severe cardiac structural and functional deterioration, with higher Masson-staining score and BNP levels, and lower EF, FS, Max +dp/dt, and Max -dp/dt values; while SIRT1 overexpression had the opposite attenuating effects. In kidney, SIRT1 knockout resulted in greater structural and functional deterioration, as evidenced by more severe morphologic changes, higher levels of UACR, BUN and SCr, and increased desmin and TGF-β expression, while SIRT1 overexpression resulted in less severe morphologic changes and increased nephrin expression without significant influence on BUN or SCr levels. The SIRT1 knockout but not overexpression resulted in increased myocardial expression of CHOP and GRP78. Cardiac-specific SIRT1 knockout or overexpression resulted in increased or decreased renal expression of CHOP, Bax, and p53 respectively. Conclusions: Myocardial SIRT1 activation appears protective to both heart and kidney in CRS models, probably through modulation of ER stress.

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