β-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis: Role of β1 Integrins

Increased sympathetic nerve activity to the myocardium is a central feature in patients with heart failure. Accumulation of catecholamines plays an important role in the pathogenesis of heart disease. Acting via β-adrenergic receptors (β-AR), catecholamines (norepinephrine and isoproterenol) increase cardiac myocyte apoptosis in vitro and in vivo. Specifically, β1-AR and β2-AR coupled to Gαs exert a proapoptotic action, while β2-AR coupled to Gi exerts an antiapoptotic action. β1 integrin signaling protects cardiac myocytes against β-AR-stimulated apoptosis in vitro and in vivo. Interaction of matrix metalloproteinase-2 (MMP-2) with β1 integrins interferes with the survival signals initiated by β1 integrins. This paper will discuss background information on β-AR and integrin signaling and summarize the role of β1 integrins in β-AR-stimulated cardiac myocyte apoptosis.

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Long Noncoding RNA TUG1/miR-29c Axis Affects Cell Proliferation, Invasion, and Migration in Human Pancreatic Cancer

Disease Markers ◽

10.1155/2018/6857042 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 18

Author(s):

Yebin Lu ◽

Ling Tang ◽

Zhipeng Zhang ◽

Shengyu Li ◽

Shuai Liang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Matrix Metalloproteinase ◽

Human Pancreatic Cancer ◽

Matrix Metalloproteinase 2 ◽

Integrin Subunit ◽

Normal Tissues

Given the low resection rate and chemoresistance of patients with pancreatic cancer (PC), their survival rates are typically poor. Long noncoding RNAs (lncRNAs) have recently been shown to play an important role in tumourigenesis and human cancer progression, including in PC. In this study, we aimed to investigate the role of taurine-upregulated gene 1 (TUG1) in PC. A quantitative polymerase chain reaction was used to analyse TUG1 expression in PC tissues and peritumoural normal tissues. TUG1 was overexpressed in PC tissues compared with that in peritumoural normal tissues, and the high expression of TUG1 was associated with the poor prognosis of patients with PC. Furthermore, TUG1 knockdown significantly inhibited the proliferation and invasion of PC cells both in vitro and in vivo, while overexpression TUG1 promoted tumour cell proliferation, migration, and invasion. TUG1 directly targeted miR-29c, a tumour suppressor in several cancers. TUG1 knockdown significantly increased the expression of miR-29c and subsequently induced the downregulation of integrin subunit beta 1 (ITGB1), matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9). The downregulation of miR-29c abolished the TUG1 knockdown-mediated inhibition of tumour growth in vitro and in vivo, whereas the upregulation of miR-29c enhanced the effects of TUG1 knockdown on PC cells. In conclusion, we demonstrate for the first time the oncogenic role of TUG1 in PC. The downregulation of TUG1 significantly inhibited the growth and migratory ability of PC cells in vitro and in vivo by targeting miR-29c. Our study provides a novel potential diagnostic biomarker and therapeutic target for PC.

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Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00720.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. H985-H994 ◽

Cited By ~ 53

Author(s):

Tuanzhu Ha ◽

Fang Hua ◽

Yuehua Li ◽

Jing Ma ◽

Xiang Gao ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Function ◽

Cardiac Myocyte ◽

Pressure Overload ◽

Terminal Deoxynucleotidyl Transferase ◽

Heart Weight ◽

Aortic Banding ◽

Myocyte Apoptosis ◽

Cardiac Myocyte Apoptosis

In this study, we evaluated whether blocking myeloid differentiation factor-88 (MyD88) could decrease cardiac myocyte apoptosis following pressure overload. Adenovirus expressing dominant negative MyD88 (Ad5-dnMyD88) or Ad5-green fluorescent protein (GFP) (Ad5-GFP) was transfected into rat hearts ( n = 8/group) immediately followed by aortic banding for 3 wk. One group of rats ( n = 8) was subjected to aortic banding for 3 wk without transfection. Sham surgical operation ( n = 8) served as control. The ratios of heart weight to body weight (HW/BW) and heart weight to tibia length (HW/TL) were calculated. Cardiomyocyte size was examined by FITC-labeled wheat germ agglutinin staining of membranes. Cardiac myocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and myocardial interstitial fibrosis was examined by Masson's Trichrome staining. Aortic banding significantly increased the HW/BW by 41.0% (0.44 ± 0.013 vs. 0.31 ± 0.008), HW/TL by 47.2% (42.7 ± 1.30 vs. 29.0 ± 0.69), cardiac myocyte size by 49.6%, and cardiac myocyte apoptosis by 11.5%, and myocardial fibrosis and decreased cardiac function compared with sham controls. Transfection of Ad5-dnMyD88 significantly reduced the HW/BW by 18.2% (0.36 ± 0.006 vs. 0.44 ± 0.013) and HW/TL by 22.3% (33.2 ± 0.95 vs. 42.7 ± 1.30) and decreased cardiomyocyte size by 56.8%, cardiac myocyte apoptosis by 76.2%, as well as fibrosis, and improved cardiac function compared with aortic-banded group. Our results suggest that MyD88 is an important component in the Toll-like receptor-4-mediated nuclear factor-κB activation pathway that contributes to the development of cardiac hypertrophy. Blockade of MyD88 significantly reduced cardiac hypertrophy, cardiac myocyte apoptosis, and improved cardiac function in vivo.

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p38 and ERK1/2 MAPKs mediate the interplay of TNF-α and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00919.2007 ◽

2007 ◽

Vol 293 (6) ◽

pp. H3524-H3531 ◽

Cited By ~ 85

Author(s):

Sanjiv Dhingra ◽

Anita K. Sharma ◽

Dinender K. Singla ◽

Pawan K. Singal

Keyword(s):

Oxidative Stress ◽

P38 Mapk ◽

Cardiac Myocyte ◽

Cell Injury ◽

Male Rats ◽

Tnf Α ◽

Myocyte Apoptosis ◽

Cardiac Myocyte Apoptosis ◽

Induced Changes

It is known that TNF-α increases the production of ROS and decreases antioxidant enzymes, resulting in an increase in oxidative stress. IL-10 appears to modulate these effects. The present study investigated the role of p38 and ERK1/2 MAPKs in mediating the interplay of TNF-α and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis in Sprague-Dawley male rats. Isolated adult cardiac myocytes were exposed to TNF-α (10 ng/ml), IL-10 (10 ng/ml), and IL-10 + TNF-α ( ratio 1) for 4 h. H2O2(100 μM) as a positive control and the antioxidant Trolox (20 μmol/l) were used to confirm the involvement of oxidative stress. H2O2treatment increased oxidative stress and apoptosis; TNF-α mimicked these effects. Exposure to TNF-α significantly increased ROS production, caused cell injury, and increased the number of apoptotic cells and Bax-to-Bcl-xl ratio. This change was associated with an increase in the phospho-p38 MAPK-to-total p38 MAPK ratio and a decrease in the phospho-ERK1/2-to-total ERK1/2 ratio. IL-10 treatment by itself had no effect on these parameters, but it prevented the above-listed changes caused by TNF-α. The antioxidant Trolox modulated TNF-α-induced changes in Bax/Bcl-xl, cell injury, and MAPKs. Preexposure of cells to the p38 MAPK inhibitor SB-203580 prevented TNF-α-induced changes. Inhibition of the ERK pathway with PD-98059 attenuated the protective role of IL-10 against TNF-α-induced apoptosis. This study provides evidence in support of the essential role of p38 and ERK1/2 MAPKs in the interactive role of TNF-α and IL-10 in cardiac myocyte apoptosis.

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Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review

Circulation ◽

10.1161/circulationaha.121.055890 ◽

2021 ◽

Vol 144 (20) ◽

pp. 1646-1655

Author(s):

Babken Asatryan ◽

Angeliki Asimaki ◽

Andrew P. Landstrom ◽

Mohammed Y. Khanji ◽

Katja E. Odening ◽

...

Keyword(s):

Immune Response ◽

Cardiac Myocyte ◽

Clinical Investigation ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Incomplete Penetrance ◽

Arrhythmogenic Cardiomyopathy ◽

Premature Ventricular Contractions

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti–desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

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Matrix metalloproteinase‐2 contributes to hydrogen peroxide induced cardiac myocyte apoptosis

The FASEB Journal ◽

10.1096/fasebj.22.2_supplement.645 ◽

2008 ◽

Vol 22 (S2) ◽

pp. 645-645

Author(s):

Mohammad Abdel‐Motaal Ali ◽

Miranda Sung ◽

Thanh Tran ◽

Bryan Crawford ◽

Cory Rosenfelt ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Matrix Metalloproteinase ◽

Cardiac Myocyte ◽

Matrix Metalloproteinase 2 ◽

Myocyte Apoptosis ◽

Cardiac Myocyte Apoptosis

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Burn plasma mediates cardiac myocyte apoptosis via endotoxin

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00393.2001 ◽

2002 ◽

Vol 282 (5) ◽

pp. H1907-H1914 ◽

Cited By ~ 41

Author(s):

Deborah L. Carlson ◽

Ellis Lightfoot ◽

Debora D. Bryant ◽

Sandra B. Haudek ◽

David Maass ◽

...

Keyword(s):

Primary Culture ◽

Caspase 3 ◽

Cardiac Myocyte ◽

Enzyme Linked Immunosorbent Assay ◽

Tnf Α ◽

Apoptotic Effect ◽

Myocyte Apoptosis ◽

Cardiac Myocyte Apoptosis ◽

Factor Α

Thermal trauma is associated with cardiac myocyte apoptosis in vivo. To determine whether cardiac myocyte apoptosis could be secondary to burn-induced cytokines or inflammatory mediators, we investigated the effects of tumor necrosis factor-α (TNF-α) and burn plasma on a murine cardiac myocyte cell line and primary culture myocytes. HL-1 cells were exposed to plasma isolated from burned or sham rats. Burn, but not sham plasma, induced significant increases in caspase-3 activity and DNA fragmentation. Similar results were obtained in primary culture rat myocytes. A dose-dependent increase in caspase-3 activity was observed when HL-1 cells were incubated with increasing concentrations of TNF-α. Even though TNF-α increased apoptosis, enzyme-linked immunosorbent assay detected no TNF-α in burn plasma. Burn plasma also failed to induce TNF-α mRNA, eliminating an autocrine mechanism of TNF-α secretion and binding. Also, treatment of burn plasma containing rhuTNFR:Fc failed to inhibit apoptosis. To examine the possibility that endotoxin within burn plasma might account for the apoptotic effect, burn plasma was preincubated with rBPI21. Caspase-3 activity was reduced to control levels. These data indicate that burn plasma induces apoptosis in cardiac myocytes via an endotoxin-dependent mechanism and suggest that systemic inhibition of endotoxin may provide a therapeutic approach for treatment of burn-associated cardiac dysfunction.

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The Long Noncoding RNA Hotair Regulates Oxidative Stress and Cardiac Myocyte Apoptosis during Ischemia-Reperfusion Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/1645249 ◽

2020 ◽

Vol 2020 ◽

pp. 1-19 ◽

Cited By ~ 3

Author(s):

Kai Meng ◽

Jiao Jiao ◽

Rui-Rui Zhu ◽

Bo-Yuan Wang ◽

Xiao-Bo Mao ◽

...

Keyword(s):

Oxidative Stress ◽

Calcium Binding ◽

Cardiac Myocyte ◽

Heart Diseases ◽

Ischemia Reperfusion ◽

Negative Regulator ◽

Dependent Manner ◽

Myocyte Apoptosis ◽

Cardiac Myocyte Apoptosis

Oxidative stress and subsequent cardiac myocyte apoptosis play central roles in the initiation and progression of myocardial ischemia-reperfusion (I/R) injury. Homeobox transcript antisense intergenic RNA (Hotair) was previously implicated in various heart diseases, yet its role in myocardial I/R injury has not been clearly demonstrated. Mice with cardiac-restricted knockdown or overexpression of Hotair were exposed to I/R surgery. H9c2 cells were cultured and subjected to hypoxia/reoxygenation (H/R) stimulation to further verify the role and underlying mechanisms of Hotair in vitro. Histological examination, molecular detection, and functional parameters were determined in vivo and in vitro. In response to I/R or H/R treatment, Hotair expression was increased in a bromodomain-containing protein 4-dependent manner. Cardiac-restricted knockdown of Hotair exacerbated, whereas Hotair overexpression prevented I/R-induced oxidative stress, cardiac myocyte apoptosis, and cardiac dysfunction. Mechanistically, we observed that Hotair exerted its beneficial effects via activating AMP-activated protein kinase alpha (AMPKα). Further detection revealed that Hotair activated AMPKα through regulating the enhancer of zeste homolog 2/microRNA-451/calcium-binding protein 39 (EZH2/miR-451/Cab39) axis. We provide the evidence that endogenous lncRNA Hotair is an essential negative regulator for oxidative stress and cardiac myocyte apoptosis in myocardial I/R injury, which is dependent on AMPKα activation via the EZH2/miR-451/Cab39 axis.

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