scholarly journals Diallyl Trisulfide (DATS) Suppresses AGE-Induced Cardiomyocyte Apoptosis by Targeting ROS-Mediated PKCδ Activation

2020 ◽  
Vol 21 (7) ◽  
pp. 2608
Author(s):  
Dennis Jine-Yuan Hsieh ◽  
Shang-Chuan Ng ◽  
Ren-You Zeng ◽  
Viswanadha Vijaya Padma ◽  
Chih-Yang Huang ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Cells ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
Ros Generation ◽  
Diallyl Trisulfide ◽  
Glycation End Products ◽  
Glucose Exposure ◽  
Induced Apoptosis ◽  
Related Proteins

Chronic high-glucose exposure results in the production of advanced glycation end-products (AGEs) leading to reactive oxygen species (ROS) generation, which contributes to the development of diabetic cardiomyopathy. PKCδ activation leading to ROS production and mitochondrial dysfunction involved in AGE-induced cardiomyocyte apoptosis was reported in our previous study. Diallyl trisulfide (DATS) is a natural cytoprotective compound under various stress conditions. In this study, the cardioprotective effect of DATS against rat streptozotocin (STZ)-induced diabetic mellitus (DM) and AGE-induced H9c2 cardiomyoblast cell/neonatal rat ventricular myocyte (NRVM) damage was assessed. We observed that DATS treatment led to a dose-dependent increase in cell viability and decreased levels of ROS, inhibition of PKCδ activation, and recuded apoptosis-related proteins. Most importantly, DATS reduced PKCδ mitochondrial translocation induced by AGE. However, apoptosis was not inhibited by DATS in cells transfected with PKCδ-wild type (WT). Inhibition of PKCδ by PKCδ-kinase-deficient (KD) or rottlerin not only inhibited cardiac PKCδ activation but also attenuated cardiac cell apoptosis. Interestingly, overexpression of PKCδ-WT plasmids reversed the inhibitory effects of DATS on PKCδ activation and apoptosis in cardiac cells exposed to AGE, indicating that DATS may inhibit AGE-induced apoptosis by downregulating PKCδ activation. Similar results were observed in AGE-induced NRVM cells and STZ-treated DM rats following DATS administration. Taken together, our results suggested that DATS reduced AGE-induced cardiomyocyte apoptosis by eliminating ROS and downstream PKCδ signaling, suggesting that DATS has potential in diabetic cardiomyopathy (DCM) treatment.

Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs)-Exosome Carrying MiRNA-312 Inhibits Sevoflurane-Induced Cardiomyocyte Apoptosis Through Activation of Phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/AKT) Pathway

2022 ◽  
Vol 12 (5) ◽  
pp. 947-952
Author(s):  
Jun Zhang ◽  
Yuying Gao ◽  
Peng Chen ◽  
Yu Zhou ◽  
Sheng Guo ◽  
...  
Keyword(s):  
Protein Kinase B ◽  
Cardiomyocyte Apoptosis ◽  
Erk Signaling ◽  
Akt Pathway ◽  
Cardiomyocyte Proliferation ◽  
Akt Signaling Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Dmso Treatment ◽  
Induced Apoptosis ◽  
Related Proteins

This study was to explore the mechanism by how exosomes (exo) derived from BMSCs affects cardiomyocyte apoptosis. BMSCs were isolated and incubated with cardiomyocytes while the cardiomyocytes were exposed to sevoflurane or DMSO treatment. Apoptotic cells were calculated and level of apoptosis related proteins was detected by Western blot. Through transfection with microRNA-(miRNA)-312 inhibitor, we evaluated the effect of BMSC-exo on the sevoflurane-induced apoptosis. Sevoflurane significantly inhibited the viability of cardiomyocytes and induced cardiomyocyte apoptosis. Besides, sevoflurane decreased the expression of miR-312 and enhanced Bax expression in cardiomyocytes through restraining the phosphorylation of MAPK/ERK. Treatment with BMSC-exo, however, activated MAPK/ERK signaling by up-regulating miR-312, thereby inhibiting cardiomyocyte apoptosis, promoting cardiomyocyte proliferation, and elevating the level of Bcl-2. In conclusion, BMSC-exo-derived miR-312 inhibits sevoflurane-induced cardiomyocyte apoptosis by activating PI3K/AKT signaling pathway.

Abstract 028: CCN1 Enables Fas Ligand-Induced Apoptosis by Elevating Fas Expression in Primary Cardiomyocytes or by Increasing Cytoplasmic Smac in Cardiomyoblast H9c2 Cells

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Bor-Chyuan Su ◽  
Fan-E Mo
Keyword(s):  
Cell Surface ◽  
Fas Ligand ◽  
Ischemia Reperfusion ◽  
Surface Display ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Neonatal Rat ◽  
Ros Generation ◽  
H9c2 Cells ◽  
Induced Apoptosis

Fas/Fas ligand (FasL) is implicated in cardiac ischemia/reperfusion injury. However, cardiomyocytes in culture are resistant to FasL-induced apoptosis, suggesting that additional factor(s) are required for FasL-induced apoptosis. Matricellular protein CCN1 has been demonstrated to promote cytotoxicity of FasL in human skin fibroblasts. CCN1 is induced in a variety of cardiac pathologies. We assessed the hypothesis that CCN1 may be involved in the regulation of FasL-induced apoptosis in cardiomyocytes. We found that either FasL or CCN1 did not induce cell death in neonatal rat ventricular cardiomyocytes (NRVM). Interestingly, the combination of FasL+CCN1 generated 2-fold induction of apoptosis (vs. control p<0.001). An integrin-α 6 β 1 -binding defective mutant CCN1, CCN1-DM failed to exert synergy with FasL to induce apoptosis, indicating a critical role of α 6 β 1 . The engagement between CCN1 and α 6 β 1 instigated the elevation of cellular reactive oxygen species (ROS), the activation of mitogen activated protein kinase p38, and followed by the induction of cell surface display of Fas, thereby sensitizing NRVM to FasL-induced apoptosis. Pretreatment of the p38 inhibitor SB202190 abolished the CCN1-induced cell-surface Fas expression and the apoptosis induced by FasL+CCN1. In addition, we tested the interaction between CCN1 and FasL on the cardiomyoblast H9c2 cells. We found that FasL or CCN1 alone did not cause apoptosis in H9c2, and required the combination of FasL+CCN1 to induced apoptosis (vs. control p<0.001) in H9c2 cells, reminiscent of the observation in NRVM. Mechanistically, CCN1 acted through binding to integrin α 6 β 1 , ROS generation, and p38 activation, however, did not increase the expression of cell surface Fas for its synergy with FasL in H9c2 cells. Instead, CCN1 induced Bax translocation to mitochondria, which in turn led to the release of Smac from mitochondria to cytosol. The cytosolic Smac functions to neutralize XIAP. Smac is critical for CCN1 action, because the knockdown of Smac blunted the apoptotic activities of CCN1. In conclusion, CCN1 may play a detrimental role in a stressed heart to both the differentiated cardiomyocytes and the proliferative cardioblasts through distinct signaling mechanisms.

scholarly journals Apigenin Attenuates Adriamycin-Induced Cardiomyocyte Apoptosis via the PI3K/AKT/mTOR Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Wei Yu ◽  
Huirong Sun ◽  
Wenliang Zha ◽  
Weili Cui ◽  
Ling Xu ◽  
...  
Keyword(s):  
Treatment Group ◽  
Cardiac Injury ◽  
Serum Levels ◽  
Mtor Pathway ◽  
Cardiomyocyte Apoptosis ◽  
Control Group ◽  
Limiting Factor ◽  
High Dose ◽  
Induced Apoptosis ◽  
Related Proteins

Treatment with Adriamycin (ADR) is one of the major causes of chemotherapy-induced cardiotoxicity and therefore is the principal limiting factor in the effectiveness of chemotherapy for cancer patients. Apigenin (API) has been shown to play a cardioprotective role. The present study examined the effect of API on ADR-induced cardiotoxicity in mice. Sixty male Kunming mice were randomly divided into 4 groups: a control group, ADR model group, low-dose API treatment group (125 mg·kg−1), and high-dose API treatment group (250 mg·kg−1). Blood samples were taken to evaluate a spectrum of myocardial enzymes. Cardiomyocyte apoptosis was measured using a TUNEL assay, and cardiomyocyte autophagy was observed using electron microscopy. Moreover, apoptosis-related proteins, such as Bax and Bcl-2, autophagy-related proteins, including Beclin1 and LC3B, and PI3K/AKT/mTOR pathway-related proteins were examined with western blot. Our results demonstrate that ADR caused an increase in the serum levels of cardiac injury markers and enhanced cardiomyocyte apoptosis and autophagy. API administration prevented the effects associated with ADR-induced cardiotoxicity in mice and inhibited ADR-induced apoptosis and autophagy. API also promoted PI3K/AKT/mTOR pathway activity in ADR-treated mice. In conclusion, API may have a protective effect against ADR-induced cardiotoxicity by inhibiting apoptosis and autophagy via activation of the PI3K/AKT/mTOR pathway.

scholarly journals Autophagy Protects Advanced Glycation End Product-Induced Apoptosis and Expression of MMP-3 and MMP-13 in Rat Chondrocytes

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Wenzhou Huang ◽  
Peng Ao ◽  
Jian Li ◽  
Tianlong Wu ◽  
Libiao Xu ◽  
...  
Keyword(s):  
Western Blotting ◽  
Annexin V ◽  
Protective Role ◽  
Autophagic Flux ◽  
Advanced Glycation ◽  
Age Related ◽  
Glycation End Products ◽  
Induced Apoptosis ◽  
Related Proteins

Aging is one of the most prominent risk factors for the pathological progression of osteoarthritis (OA). One feature of age-related changes in OA is advanced glycation end products (AGEs) accumulation in articular cartilage. Autophagy plays a cellular housekeeping role by removing dysfunctional cellular organelles and proteins. However, the relationship between autophagy and AGE-associated OA is unknown. The aim of this study is to determine whether autophagy participates in the pathology of AGE-treated chondrocytes and to investigate the exact role of autophagy in AGE-induced cell apoptosis and expression of matrix metalloproteinase- (MMP-) 3 and MMP-13. AGEs induced notable apoptosis that was detected by Annexin V/PI double-staining, and the upregulation of MMP-3 and MMP-13 was confirmed by Western blotting. Autophagy-related proteins were also determined by Western blotting, and chondrocytes were transfected with mCherry-GFP-LC3B-adenovirus to monitor autophagic flux. As a result, autophagy significantly increased in chondrocytes and peaked at 6 h. Furthermore, rapamycin (RA) attenuated AGE-induced apoptosis and expression of MMP-3 and MMP-13 by autophagy activation. In contrast, pretreatment with autophagy inhibitor 3-methyladenine (3-MA) enhanced the abovementioned effects of AGEs. We therefore demonstrated that autophagy is linked with AGE-related pathology in rat chondrocytes and plays a protective role in AGE-induced apoptosis and expression of MMP-3 and MMP-13.

scholarly journals A novel methylated analogue of L-Mimosine exerts its therapeutic potency through ROS production and ceramide-induced apoptosis in malignant melanoma

2021 ◽  
Author(s):  
Sotiris Kyriakou ◽  
William Cheung ◽  
Theodora Mantso ◽  
Melina Mitsiogianni ◽  
Ioannis Anestopoulos ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Caspase 3 ◽  
Ros Generation ◽  
Alamar Blue ◽  
Intrinsic Apoptosis ◽  
Membrane Depolarisation ◽  
Induced Apoptosis ◽  
Related Proteins ◽  
Metabolomic Approach

Abstract Melanoma is an aggressive and highly metastatic type of skin cancer where the design of new therapies is of utmost importance for the clinical management of the disease. Thus, we have aimed to investigate the mode of action by which a novel methylated analogue of L-Mimosine (e.g., L-SK-4) exerts its therapeutic potency in an in vitro model of malignant melanoma. Cytotoxicity was assessed by the Alamar Blue assay, oxidative stress by commercially available kits, ROS generation, caspase 3/7 activation and mitochondrial membrane depolarisation by flow cytometry, expression of apoptosis-related proteins by western immunoblotting and profiling of lipid biosynthesis by a metabolomic approach. Overall, higher levels of ROS, sphingolipids and apoptosis were induced by L-SK-4 suggesting that the compound’s therapeutic potency is mediated through elevated ROS levels which promote the upregulation of sphingolipid (ceramide) biosynthesis thus leading to the activation of both extrinsic and intrinsic apoptosis, in an experimental model of malignant melanoma.

Liver X receptor α is targeted by microRNA-1 to inhibit cardiomyocyte apoptosis through a ROS-mediated mitochondrial pathway

2018 ◽  
Vol 96 (1) ◽  
pp. 11-18 ◽  
Author(s):  
Yongxia Cheng ◽  
Dawei Zhang ◽  
Min Zhu ◽  
Ying Wang ◽  
Sufen Guo ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Mitochondrial Pathway ◽  
Liver X Receptor ◽  
Cardiomyocyte Apoptosis ◽  
H9c2 Cells ◽  
Upstream Regulator ◽  
Liver X Receptor Α ◽  
Artery Disease ◽  
Induced Apoptosis ◽  
Related Proteins

Diabetic cardiomyopathy (DCM) is defined as ventricular dysfunction occurring independently of a recognized cause such as hypertension or coronary artery disease. Liver X receptor α (LXRα), a subtype of ligand-activated transcription factors LXRs, has been considered as a potential pharmacological target in the pathogenesis of cardiovascular and metabolic diseases. However, the potential mechanism of how LXRα is regulated in cardiomyocytes is still unclear. This study investigated the effect of activating LXRα with GW3965 on cardiomyocyte apoptosis and its upstream regulator in glucose-induced H9C2 cells. Our data indicated that GW3965 up-regulated the expression of LXRα, inhibited cardiomyocyte apoptosis, and altered the apoptosis-related proteins in glucose-induced H9C2 cells. In addition, GW3965 restored the mitochondrial membrane potential level and decreased the ROS production induced by glucose. Moreover, LXRα was confirmed as a direct target of microRNA-1 (miR-1) that was involved in cardiomyocyte apoptosis of DCM, and overexpression of miR-1 abrogated the inhibiting effect of GW3965 on glucose-induced apoptosis in H9C2 cells. This study highlights an important role of LXRα in the development of DCM and brings new insights into the complex mechanisms involved in the pathogenesis of DCM.

scholarly journals H11 has dose-dependent and dual hypertrophic and proapoptotic functions in cardiac myocytes

2005 ◽  
Vol 388 (2) ◽  
pp. 475-483 ◽  
Author(s):  
Makoto HASE ◽  
Christophe DEPRE ◽  
Stephen F. VATNER ◽  
Junichi SADOSHIMA
Keyword(s):  
Cardiac Myocytes ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Common Mechanism ◽  
Dual Function ◽  
Physical Interaction ◽  
Low Doses ◽  
Α Subunit ◽  
High Doses ◽  
Induced Apoptosis

We have shown previously that H11, a serine/threonine kinase, is up-regulated in a heart subjected to ischaemia/reperfusion. In the present study, we have characterized the cellular function of H11, using neonatal rat cardiac myocytes. Although transduction of adenovirus harbouring H11 at low doses increased the cell size, at higher doses it induced apoptosis in cardiac myocytes. Apoptosis was not observed when adenovirus harbouring H11-KI (kinase-inactive mutant of H11) was used, suggesting that the proapoptotic effect of H11 is kinase-dependent. The hypertrophic effect of H11 at high doses was unmasked when apoptosis was inhibited by the caspase inhibitor DEVD-CHO, suggesting that H11 stimulates both hypertrophy and apoptosis in parallel. H11-KI induced hypertrophy even at high doses, indicating that H11 stimulates hypertrophy through kinase-independent mechanisms. H11-KI activated Akt, and cardiac hypertrophy induced by H11-KI was blocked by LY294002, an inhibitor of phosphoinositide 3-kinase. Co-immunoprecipitation analyses indicated that H11 interacts with the α subunit of CK2 (casein kinase 2). Overexpression of H11 decreased the kinase activity of CK2. DRB (5,6-dichloro-1-β-D-ribofuranosyl-benzimidazole), an inhibitor of CK2, mimicked the effect of H11, whereas DRB and H11 failed to exhibit additive effects on apoptosis, suggesting that H11 and DRB utilize a common mechanism to induce apoptosis, namely inhibition of CK2. In summary, H11 is a dual-function kinase in cardiac cells: it induces hypertrophy at low doses through kinase-independent activation of Akt, whereas it causes apoptosis at high doses through protein kinase-dependent mechanisms, in particular by physical interaction with and subsequent inhibition of CK2.

scholarly journals A novel methylated analogue of L-Mimosine exerts its therapeutic potency through ROS production and ceramide-induced apoptosis in malignant melanoma

2021 ◽  
Author(s):  
Sotiris Kyriakou ◽  
William Cheung ◽  
Theodora Mantso ◽  
Melina Mitsiogianni ◽  
Ioannis Anestopoulos ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
In Vitro Model ◽  
Ros Generation ◽  
Intrinsic Apoptosis ◽  
Membrane Depolarisation ◽  
Vitro Model ◽  
Induced Apoptosis ◽  
Related Proteins ◽  
Metabolomic Approach

SummaryMelanoma is an aggressive and highly metastatic type of skin cancer where the design of new therapies is of utmost importance for the clinical management of the disease. Thus, we have aimed to investigate the mode of action by which a novel methylated analogue of L-Mimosine (e.g., L-SK-4) exerts its therapeutic potency in an in vitro model of malignant melanoma. Cytotoxicity was assessed by the Alamar Blue assay, oxidative stress by commercially available kits, ROS generation, caspase 3/7 activation and mitochondrial membrane depolarisation by flow cytometry, expression of apoptosis-related proteins by western immunoblotting and profiling of lipid biosynthesis by a metabolomic approach. Overall, higher levels of ROS, sphingolipids and apoptosis were induced by L-SK-4 suggesting that the compound’s therapeutic potency is mediated through elevated ROS levels which promote the upregulation of sphingolipid (ceramide) biosynthesis thus leading to the activation of both extrinsic and intrinsic apoptosis, in an experimental model of malignant melanoma.

scholarly journals Otoprotective Effect of 2,3,4′,5-Tetrahydroxystilbene-2-O-β-d-Glucoside on Gentamicin-Induced Apoptosis in Mouse Cochlear UB/OC-2 Cells

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3070
Author(s):  
Yu-Hsuan Wen ◽  
Jia-Ni Lin ◽  
Rong-Shuan Wu ◽  
Szu-Hui Yu ◽  
Chuan-Jen Hsu ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Therapeutic Option ◽  
Apoptotic Cell Death ◽  
Ros Generation ◽  
Sod Activity ◽  
Ldh Release ◽  
Induced Apoptosis ◽  
Related Proteins

Excessive levels of reactive oxygen species (ROS) lead to mitochondrial damage and apoptotic cell death in gentamicin-induced ototoxicity. 2,3,4’,5-Tetrahydroxystilbene-2-O-β-d-glucoside (THSG), a bioactive constituent, isolated from Polygonum multiflorum Thunb., exhibits numerous biological benefits in treating aging-related diseases by suppressing oxidative damage. However, its protective effect on gentamicin-induced ototoxicity remains unexplored. Therefore, here, we aimed to investigate the otoprotective effect of THSG on gentamicin-induced apoptosis in mouse cochlear UB/OC-2 cells. We evaluated the effect of gentamicin and THSG on the ROS level, superoxide dismutase (SOD) activity, mitochondrial membrane potential, nuclear condensation, and lactate dehydrogenase (LDH) release, and the expression of apoptosis-related proteins was assessed to understand the molecular mechanisms underlying its preventive effects. The findings demonstrated that gentamicin increased ROS generation, LDH release, and promoted apoptotic cell death in UB/OC-2 cells. However, THSG treatment reversed these effects by suppressing ROS production and downregulating the mitochondrial-dependent apoptotic pathway. Additionally, it increased the SOD activity, decreased the expression of apoptosis-related proteins, alleviated the levels of the apoptotic cells, and impaired cytotoxicity. To the best of our knowledge, this is the first study to demonstrate that THSG could be a potential therapeutic option to attenuate gentamicin-induced ototoxicity.

Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a

2013 ◽  
Vol 304 (6) ◽  
pp. C508-C518 ◽  
Author(s):  
Craig W. Younce ◽  
Melissa A. Burmeister ◽  
Julio E. Ayala
Keyword(s):  
Endoplasmic Reticulum ◽  
Protective Effect ◽  
Er Stress ◽  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Ischemia Reperfusion ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
Protein Levels ◽  
The Unfolded Protein Response

Hyperglycemia-induced cardiomyocyte apoptosis contributes to diabetic cardiomyopathy. Glucagon-like peptide-1 (Glp1) receptor (Glp1r) agonists improve cardiac function and survival in response to ischemia-reperfusion and myocardial infarction. The present studies assessed whether Glp1r activation exerts direct cardioprotective effects in response to hyperglycemia. Treatment with the Glp1r agonist Exendin-4 attenuated apoptosis in neonatal rat ventricular cardiomyocytes cultured in high (33 mM) glucose. This protective effect was mimicked by the cAMP inducer forskolin. The Exendin-4 protective effect was blocked by the Glp1r antagonist Exendin(9-39) or the PKA antagonist H-89. Exendin-4 also protected cardiomyocytes from hydrogen peroxide (H2O2)-induced cell death. Cardiomyocyte protection by Exendin-4 was not due to reduced reactive oxygen species levels. Instead, Exendin-4 treatment reduced endoplasmic reticulum (ER) stress, demonstrated by decreased expression of glucose-regulated protein-78 (GRP78) and CCAT/enhancer-binding homologous protein (CHOP). Reduced ER stress was not due to activation of the unfolded protein response, indicating that Exendin-4 directly prevents ER stress. Exendin-4 treatment selectively protected cardiomyocytes from thapsigargin- but not tunicamycin-induced death. This suggests that Exendin-4 attenuates thapsigargin-mediated inhibition of the sarco/endoplasmic reticulum Ca2+ ATPase-2a (SERCA2a). High glucose attenuates SERCA2a function by reducing SERCA2a mRNA and protein levels, but Exendin-4 treatment prevented this reduction. Exendin-4 treatment also enhanced phosphorylation of the SERCA2a regulator phospholamban (PLN), which would be expected to stimulate SERCA2a activity. In sum, Glp1r activation attenuates high glucose-induced cardiomyocyte apoptosis in association with decreased ER stress and markers of enhanced SERCA2a activity. These findings identify a novel mechanism whereby Glp1-based therapies could be used as treatments for diabetic cardiomyopathy.

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