Quercetin improve ischemia/reperfusion‐induced cardiomyocyte apoptosis in vitro and in vivo study via SIRT1/PGC‐1α signaling

2019 ◽  
Vol 120 (6) ◽  
pp. 9747-9757 ◽  
Author(s):  
Jiayou Tang ◽  
Linhe Lu ◽  
Yang Liu ◽  
Jipeng Ma ◽  
Lifang Yang ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Cardiomyocyte Apoptosis ◽  
In Vivo Study

Abstract 1949: The Protein Kinase MAP4K4 Is Activated in Failing Human Hearts and Mediates Cardiomyocyte Apoptosis in Experimental Models, in vitro and in vivo

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Min Xie ◽  
Dou Zhang ◽  
Sam C Wang ◽  
Motoaki Sano ◽  
XiaoZhen Wang ◽  
...  
Keyword(s):  
Rna Interference ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Experimental Models ◽  
Cardiomyocyte Apoptosis ◽  
Cancer Drug ◽  
Transgenic Expression ◽  
Cultured Cardiomyocytes

Mitogen-activated protein kinases (MAPKs) have been implicated in cardiac muscle hypertrophy, apoptosis, and heart failure, but relatively little is known of the proximal MAP4Ks that might couple cardiac stress signals to downstream effector kinases. Previously we have shown that epitope-tagged MAP4K4 (hematopoietic progenitor kinase/germinal center kinase-like kinase, HGK) was activated by diverse apoptotic signals in cultured cardiomyocytes and transgenic mouse hearts. Here, we report results for the activation of MAP4K4 in the hearts of patients undergoing therapeutic transplantation, and for the functional consequences of disrupting endogenous MAP4K4 by RNA interference. Compared with 10 control donor hearts obtained at overlapping ages, MAP4K4 activity increased in all subjects with dilated (4.5-fold; N = 13), hypertrophic (4-fold; N = 5), ischemic (2.5-fold; N = 6) and adriamycin-induced cardiomyopathy (3-fold, N = 2; p < 0.001 for all four groups). Activity of the MAP4K4 target, TGFbeta-activated kinase-1 (TAK1/MAP3K7), and the executioner caspase, caspase-3, increased concordantly in all subjects. In mouse myocardium, each of four biological signals for cardiomyocyte apoptosis induced the kinase activity of MAP4K4: biomechanical stress, ischemia/reperfusion injury, and gain-of-function mutations for TNFalpha and Gq. Analogous results were seen in cultured cardiomyocytes, using oxidative stress, ceramide and the cardiotoxic anti-cancer drug doxorubicin. Transgenic expression of MAP4K4 in myocardium produced little or no baseline phenotype, but markedly sensitized the myocardium to apoptosis caused by Gq. In culture, we proved that MAP4K4 induces apoptosis via TAK1, JNK, and the mitochondrial death pathway. As predicted, ceramide-induced and hydrogen peroxide-induced apoptosis was suppressed using RNA interference to silence expression of MAP4K4. Thus, MAP4K4 is activated in response to many specific cardiac death signals, and mediates cardiac apoptosis in vitro and in vivo. The prevalent activation of MAP4K4 in failing human hearts and the pro-death actions of the kinase suggest that MAP4K4 is a possible therapeutic target in the treatment of apoptotic cardiomyopathies.

Involvement of MicroRNA-133a in the Protective Effect of Hydrogen Sulfide against Ischemia/Reperfusion-Induced Endoplasmic Reticulum Stress and Cardiomyocyte Apoptosis

Pharmacology ◽  
2018 ◽  
Vol 103 (1-2) ◽  
pp. 1-9 ◽  
Author(s):  
Lin Ren ◽  
Qian Wang ◽  
Yu Chen ◽  
Yanzhuo Ma ◽  
Dongmei Wang
Keyword(s):  
Hydrogen Sulfide ◽  
Protective Effect ◽  
Er Stress ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Annexin V ◽  
Cardiomyocyte Apoptosis ◽  
Migration And Invasion

Aim: Myocardial ischemia/reperfusion (I/R) injury is a severe trauma that cells undergo and is associated with cardiomyocyte apoptosis. Recently, miRNAs have been demonstrated to play an important role in cardiovascular biology and disease. However, whether the miR-133a and ER stress play a role in hydrogen sulfide (H2S) protection of cardiomyocytes against I/R-induced apoptosis remains unclear. Methods: The neonatal cardiomyocytes were prepared to be treated with H2S or transfected with miR-133a activator or miR-133a inhibitor, either separately or in combination. Non-treated cardiomyocytes served as control. The ER stress biomarker GRP78, CHOP, and eIF2α expression levels were measured by Western blot. Cell apoptosis was assessed by flow cytometry after staining with the Annexin V- FITC. Proliferation was monitored by BrdU labeling, while cell migration and invasion were determined by Transwell assays. Results: Pre-treatment of H2S and overexpression of miR-133a reversed I/R-induced ER stress and cardiomyocyte apoptosis in vitro and in vivo. The proliferation, migration, and invasion of cardiomyocytes were significantly increased by co-treatment with H2S and overexpression of miR-133a. Conclusion: These findings suggest the protective effect of miR-133a against I/R-induced ER stress and cardiomyocyte apoptosis and its enhancement of cell motility. Thus, cardioprotection by miR-133a overexpression provides a novel therapeutic approach to the treatment of ischemic heart diseases.

miR-187 Modulates Cardiomyocyte Apoptosis and Oxidative Stress in Myocardial Infarction Mice via Negatively Regulating DYRK2

2021 ◽  
Author(s):  
Fen Zhu ◽  
Zhili Yu ◽  
Dongsheng Li
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Protective Effect ◽  
Ischemia Reperfusion ◽  
Annexin V ◽  
Cardiomyocyte Apoptosis ◽  
Ros Generation ◽  
And Oxidative Stress

Abstract Background: Myocardial infarction is a serious representation of cardiovescular disease, however, ischemia–reperfusion (I/R) injury is an unpredictable complication of cardiovascular surgeries.Methods: MiR-187 or DYRK2 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with miR-187 mimic or inhibitor or DYRK2 inhibitor to confirm the function of miR-187 in H/R. A myocardium I/R mouse model was established using miR-187 transgenic mice. Circulating levels of miR-187 or DYRK2 was detected by quantitative realtime PCR and protein expression was detected by western blotting. The cell viability in all groups was determined by MTT assay and the apoptosis ratio was detected by flow cytometry after staining with Annexin V-FITC. The effect of miR-187 on cellular ROS generation was examined by DCFH-DA. The level of lipid peroxidation and SOD expression were determined by MDA and SOD assay. Results: The findings indicated that miR-187 may be a possible regulator in the protective effect of H/R-induced cardiomyocyte apoptosis, cellular oxidative stress and leaded to DYRK2 suppression at a posttranscriptional level. Moreover, the improvement of miR-187 on H/R-induced cardiomyocyte injury contributed to the obstruction of DYRK2 expression. In addition, these results identified DYRK2 as the functional downstream target of miR-187 regulated myocardial infarction and oxidative stress. Conclusions: These present work provided the first insight into the function of miR-187 in successfully protect cardiomyocyte both in vivo and in vitro, and such a protective effect were mediated through the regulation of DYRK2 expression. Trial registration: Not Applicable.

scholarly journals SOCS-6 promotes mitochondrial fission and cardiomyocyte apoptosis and is negatively regulated by QKI mediated miR-19b

2020 ◽  
Author(s):  
Peng Zhang ◽  
Ping Guan ◽  
Xiaomiao Ye ◽  
Yi Lu ◽  
Yanwen Hang ◽  
...  
Keyword(s):  
Rna Binding ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Vital Role ◽  
Cardiomyocyte Apoptosis ◽  
Luciferase Assay ◽  
Future Research

Abstract Background Ischemia/reperfusion (IR) injury following myocardial infarction can result in debilitating complications and morbidity. Mitochondrial dysfunction and abnormal mitochondrial fission have been implicated in the complications associated with IR injury as cardiomyocytes are abundant in mitochondria. SOCS-6 is known to participate in mitochondrial fragmentation but its exact involvement and the pathways associated are uncertain. Results In the present study, we examine the biological role and regulation of SOCS-6 in mitochondrial dynamics using hypoxia and reoxygenation (H/R) in cardiomyocytes and with a murine model of IR injury. We found that SOCS-6 inhibition by RNA interference attenuated H/R-induced mitochondrial fission and apoptosis in cardiomyocytes. A luciferase assay indicated that SOCS-6 is a direct target of miR-19b. The overexpression of miR-19b decreased mitochondrial fission and apoptosis in vitro . Moreover, the presence of miR-19b reduced the level of SOCS-6 and the injury caused by IR in vivo . There were less apoptotic cells in the myocardium of mice injected with miR-19b. In addition, we found that the RNA-binding protein, QKI, participates in the regulation of miR-19b expression. Conclusions Our results indicate that the inhibition of mitochondrial fission through downregulating SOCS-6 via the QKI/miR-19b/SOCS-6 pathway attenuated the damage sustained by IR. The QKI/miR-19b/SOCS-6 axis plays a vital role in regulation of mitochondrial fission and cardiomyocyte apoptosis and could form the basis of future research in the development of therapies for the management of cardiac diseases.

Formulation and Evaluation of Atorvastatin Calcium-Poly-ε-Caprolactone Nanoparticles Loaded Ocular Inserts for Sustained Release and Antiinflammatory Efficacy

2020 ◽  
Vol 21 (15) ◽  
pp. 1688-1698
Author(s):  
Germeen N.S. Girgis
Keyword(s):  
Sustained Release ◽  
In Vitro Release ◽  
Pluronic F127 ◽  
In Vivo Study ◽  
Average Weight ◽  
Drug Release Profile ◽  
Atorvastatin Calcium ◽  
Anti Inflammatory

Purpose: The work was performed to investigate the feasibility of preparing ocular inserts loaded with Poly-ε-Caprolactone (PCL) nanoparticles as a sustained ocular delivery system. Methods: First, Atorvastatin Calcium-Poly-ε-Caprolactone (ATC-PCL) nanoparticles were prepared and characterized. Then, the optimized nanoparticles were loaded within inserts formulated with Methylcellulose (MC) and Polyvinyl Alcohol (PVA) by a solvent casting technique and evaluated physically, for in-vitro drug release profile. Finally, an in-vivo study was performed on the selected formulation to prove non-irritability and sustained ocular anti-inflammatory efficacy compared with free drug-loaded ocuserts. Results: The results revealed (ATC-PCL) nanoparticles prepared with 0.5% pluronic F127 were optimized with 181.72±3.6 nm particle size, 0.12±0.02 (PDI) analysis, -27.4± 0.69 mV zeta potential and 62.41%±4.7% entrapment efficiency. Nanoparticles loaded ocuserts manifested compatibility between drug and formulation polymers. Moreover, formulations complied with average weight 0.055±0.002 to 0.143±0.023 mg, and accepted pH. ATC-PCL nanoparticles loaded inserts prepared by 5% MC showed more sustained, prolonged in-vitro release over 24h. In-vivo study emphasized non-irritability, ocular anti-inflammatory effectiveness represented by smaller lid closure scores, and statistically significant lowering in PMN count after 3h. Conclusion: These findings proposed a possibly simple, new and affordable price technique to prepare promising (ATC-PCL) nanoparticles loaded inserts to achieve sustained release with prolonged antiinflammatory efficacy.

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