scholarly journals SIRT1 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the Oxidative Stress and p38MAPK Pathways

2015 ◽  
Vol 35 (3) ◽  
pp. 1116-1124 ◽  
Author(s):  
Yang Ruan ◽  
Chunlin Dong ◽  
Jigar Patel ◽  
Chao Duan ◽  
Xinyue Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cell Survival ◽  
Cell Apoptosis ◽  
Heart Function ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
Signal Pathways ◽  
Ros Production ◽  
Sirt1 Expression

Background: SIRT1, which belongs to the Sirtuin family of NAD-dependent enzymes, plays diverse roles in aging, metabolism, and disease biology. It could regulate cell survival and has been shown to be a protective factor in heart function. Hence, we verified the mechanism by which SIRT1 regulates doxorubicin induced cardiomyocyte injury in vivo and in vitro. Methods: We analyzed SIRT1 expression in doxorubicin-induced neonatal rat cardiomyocyte injury model and adult mouse heart failure model. SIRT1 was over-expressed in cultured neonatal rat cardiomyocyte by adenovirus mediated gene transfer. SIRT1 agonist resveratrol was used to treat the doxorubicin-induced heart failure mouse model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, qRT-PCR, and Western blotting were performed to analyze cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes. Results: SIRT1 expression was down-regulated in doxorubicin induced cardiomocyte injury, accompanied by elevated oxidative stress and cell apoptosis. SIRT1 over-expression reduced doxorubicin induced cardiomyocyte apoptosis with the attenuated ROS production. SIRT1 also reduced cell apoptosis by inhibition of p38MAPK phosphorylation and caspase-3 activation. The SIRT1 agonist resveratrol was able to prevent doxorubicin-induced heart function loss. Moreover, the SIRT1 inhibitor niacinamide could reverse SIRT1's protective effect in cultured neonatal rat cardiomyocytes. Conclusions: These results support the role of SIRT1 as an important regulator of cardiomyocyte apoptosis during doxorubicin-induced heart injury, which may represent a potential therapeutic target for doxorubicin-induced cardiomyopathy.

scholarly journals AstragalusPolysaccharide Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the PI3k/Akt and p38MAPK Pathways

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Yuan Cao ◽  
Yang Ruan ◽  
Tao Shen ◽  
Xiuqing Huang ◽  
Meng Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Neonatal Rat ◽  
Ros Generation ◽  
Signal Pathways ◽  
Mouse Heart ◽  
Protective Effects ◽  
Injury Model ◽  
Underlying Mechanisms ◽  
Heart Failure Model

Background. Doxorubicin, a potent chemotherapeutic agent, is associated with acute and chronic cardiotoxicity, which is cumulatively dose-dependent.Astragaluspolysaccharide (APS), the extract ofAstragalus membranaceuswith strong antitumor and antiglomerulonephritis activity, can effectively alleviate inflammation. However, whether APS could ameliorate chemotherapy-induced cardiotoxicity is not understood. Here, we investigated the protective effects of APS on doxorubicin-induced cardiotoxicity and elucidated the underlying mechanisms of the protective effects of APS.Methods. We analyzed myocardial injury in cancer patients who underwent doxorubicin chemotherapy and generated a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, DNA laddering, and Western blotting were performed to observe cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes.Results. Treatment of patients with the chemotherapeutic drug doxorubicin led to heart dysfunction. Doxorubicin reduced cardiomyocyte viability and induced C57BL/6J mouse heart failure with concurrent elevated ROS generation and apoptosis, which, however, was attenuated by APS treatment. In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment.Conclusions. These results demonstrate that APS could suppress oxidative stress and apoptosis, ameliorating doxorubicin-mediated cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways.

Abstract 424: Loss of Sirt2 Protects Against Pressure Overload- and Ischemic Reperfusion Injury-induced Cardiac Dysfunction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Teruki Sato ◽  
Xiaoyan Yan ◽  
Hsiang-Chun Chang ◽  
Chen Chunlei ◽  
Jason S Shapiro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Reperfusion Injury ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Cardiac Response ◽  
Neonatal Rat ◽  
Ros Production ◽  
Wild Type ◽  
Stress Injury

Introduction: Sirtuins are NAD+ dependent deacetylases and critical regulators of energy metabolism and response to oxidative stress. Sirtuin2 (SIRT2) is a cytoplasmic member of the sirtuin family, and has been shown to regulate cellular iron homeostasis through deacetylation of nuclear factor erythroid-derived 2-related factor 2 (NRF2). However, whether SIRT2-NRF2 pathway is involved in the development of heart failure remains unknown. Methods and results: To investigate the functional role of SIRT2 in the response to cardiac stress, SIRT2 knockout (KO) mice and their littermate controls were subjected to pressure overload by transverse aortic constriction (TAC). SIRT2 KO had normal appearance and cardiovascular parameters at baseline. However, in response to TAC, Sirt2 -/- mice displayed resistance to the pathological hypertrophic response, whereas wild type (WT) mice developed cardiac hypertrophy and heart failure. In addition, SIRT2 KO mice displayed less cardiac damage after /reperfusion injury. SIRT2 knockdown in neonatal rat cardiomyocytes (NRCM) reduced reactive oxygen species (ROS) production and cell death after H2O2 treatment. Since cellular oxidative stress is one of major contributor of cardiac dysfunction caused by both I/R injury and pressure overload, we examined whether NRF2 is associated with SIRT2-mediated cardiac response to oxidative stress. Levels of NRF2 was upregulated in NRCM with SIRT2 knockdown and treated with H2O2 compared to wild type (WT) cells. Moreover, NRF2 is translocated into the nucleus and its anti-oxidant target proteins are upregulated in NRCM with SIRT2 knockdown. SIRT2 was also found to bind and deacetylate NRF2 directly as determined by co-immunoprecipitation studies. This led to a reduction of its nuclear translocation and transcriptional activity. Finally, knockdown of both SIRT2 and NRF2 diminished the effects of SIRT2 knockdown on ROS production and cellular damage. Conclusion: These results indicate that SIRT2 contributes to pressure overload and I/R injury induced heart impairment in mice, and promotes oxidative stress injury in cardiomyocytes via deacetylating NRF2 and altering its activity.

Abstract P020: A Bioengineered Neonatal Cardiomyocyte Scaffold Promotes Cell Survival and Improves Left Ventricular Function in Rats with Heart Failure

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Jordan Lancaster ◽  
Elizabeth Juneman ◽  
Nicholle Johnson ◽  
Joseph Bahl ◽  
Steven Goldman
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cell Survival ◽  
Cell Tracking ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Neonatal Cardiomyocyte

Background: Cell-based regenerative therapies hold promise as a new treatment for heart failure. Tissue engineered scaffolds used for cell delivery enhance potential improvements in cardiac function by providing the structural and nutrient support for transplanted cell survival, integration, and re-population of injured tissues. Previously, our laboratory reported improvements in left ventricular (LV) function in rats with chronic heart failure (CHF) after placement of a neonatal cardiomyocyte (NCM) seeded 3-dimensional fibroblast construct (3DFC). In brief, 3 weeks after implantation of the NCM-3DFC, LV function improves by increasing (p<0.05) ejection fraction 26% and cardiac index 33%, while decreasing (p<0.05) LV end diastolic pressure 38%. The current report focuses on NCM survival and LV improvements out to 7 weeks post NCM-3DFC implantation. Methods and Results: Cardiomyocytes were isolated from neonatal rat hearts and seeded onto a 3DFC. We evaluated NCM-3DFC in vitro for cellular organization and the presence of functional gap junctions, which demonstrated extensive cell-to-cell connectivity. At 5 days in culture, the seeded patch contracted spontaneously in a rhythmic and directional fashion, beating at 43±3 beats/min with a mean displacement of 1.3±0.3 mm and contraction velocity of 0.8±0.2 mm/sec. The seeded patch could be electrically paced at near physiological rates (270±30 beats/min) while maintaining coordinated, directional contractions. For in vivo evaluation, rats underwent coronary artery ligation and allowed to recover for 3 weeks to establish CHF. NCM-3DFC were implanted 3 weeks after ligation and evaluated 3 and 7 weeks later (6 and 10 weeks after ligation respectively). Live cell tracking of implanted NCM using Q-Dots revealed ∼9% survival of transplanted cells 3 weeks after implantation. In addition, improvements in LV function continued at 7 weeks after implantation of the NCM-3DFC by increasing (p<0.05) ejection fraction 37%. Conclusion: A multicellular, electromechanically organized, cardiomyocyte scaffold, engineered in vitro can improve LV function when implanted directly on the hearts of rats with CHF; the transplanted cells survive and improve LV function chronically.

scholarly journals Liguzinediol improved the heart function and inhibited myocardial cell apoptosis in rats with heart failure

2014 ◽  
Vol 35 (10) ◽  
pp. 1257-1264 ◽  
Author(s):  
Yu Li ◽  
Ping Song ◽  
Qing Zhu ◽  
Qiu-yi Yin ◽  
Jia-wen Ji ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Apoptosis ◽  
Heart Function ◽  
Myocardial Cell

Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents

2015 ◽  
Vol 128 (10) ◽  
pp. 665-678 ◽  
Author(s):  
Liang Shen ◽  
Ci Chen ◽  
Xuan Wei ◽  
Xixian Li ◽  
Guangjin Luo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Mitochondrial Dysfunction ◽  
Cell Apoptosis ◽  
Pressure Overload ◽  
Ankyrin Repeat ◽  
Cardiomyocyte Apoptosis ◽  
Repeat Domain ◽  
Ankyrin Repeat Domain ◽  
P53 Activation

This study demonstrated that myocardial overexpression of Ankrd1/CARP promotes angiotensin-II- and pressure-overload-induced cell apoptosis and heart failure, with these deleterious effects being at least partly mediated by the accumulation of p53 and mitochondrial dysfunction.

OP-144 Attenuated SIRT1 Expression Correlates with Enhanced Oxidative Stress in Compensated and Decompensated Heart Failure

2015 ◽  
Vol 115 ◽  
pp. S63
Author(s):  
Feridun Akkafa ◽  
Ibrahim Halil Altıparmak ◽  
Emre Erkuş ◽  
Nurten Aksoy ◽  
Caner Kaya ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Decompensated Heart Failure ◽  
Sirt1 Expression

scholarly journals Pregnancy-associated plasma protein-aa supports hair cell survival by regulating mitochondrial function

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Mroj Alassaf ◽  
Emily C Daykin ◽  
Jaffna Mathiaparanam ◽  
Marc A Wolman
Keyword(s):  
Oxidative Stress ◽  
Hair Cell ◽  
Cell Survival ◽  
Plasma Protein ◽  
Hair Cells ◽  
Mitochondrial Function ◽  
Cell Loss ◽  
Mitochondrial Calcium ◽  
Ros Production ◽  
Stimulation Of

To support cell survival, mitochondria must balance energy production with oxidative stress. Inner ear hair cells are particularly vulnerable to oxidative stress; thus require tight mitochondrial regulation. We identified a novel molecular regulator of the hair cells’ mitochondria and survival: Pregnancy-associated plasma protein-aa (Pappaa). Hair cells in zebrafish pappaa mutants exhibit mitochondrial defects, including elevated mitochondrial calcium, transmembrane potential, and reactive oxygen species (ROS) production and reduced antioxidant expression. In pappaa mutants, hair cell death is enhanced by stimulation of mitochondrial calcium or ROS production and suppressed by a mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates extracellular insulin-like growth factor 1 (IGF1) bioavailability. We found that the pappaa mutants’ enhanced hair cell loss can be suppressed by stimulation of IGF1 availability and that Pappaa-IGF1 signaling acts post-developmentally to support hair cell survival. These results reveal Pappaa as an extracellular regulator of hair cell survival and essential mitochondrial function.

scholarly journals Modulation of Mitochondrial Quality Control Processes by BGP-15 in Oxidative Stress Scenarios: From Cell Culture to Heart Failure

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Orsolya Horvath ◽  
Katalin Ordog ◽  
Kitti Bruszt ◽  
Nikoletta Kalman ◽  
Dominika Kovacs ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Hydrogen Peroxide ◽  
Quality Control ◽  
Mitochondrial Fusion ◽  
Neonatal Rat ◽  
Failure Model ◽  
Mitochondrial Quality Control ◽  
Insulin Sensitizer ◽  
Heart Failure Model

Heart failure (HF) is a complex chronic clinical disease characterized by among others the damage of the mitochondrial network. The disruption of the mitochondrial quality control and the imbalance in fusion-fission processes lead to a lack of energy supply and, finally, to cell death. BGP-15 (O-[3-piperidino-2-hydroxy-1-propyl]-nicotinic acid amidoxime dihydrochloride) is an insulin sensitizer molecule and has a cytoprotective effect in a wide variety of experimental models. In our recent work, we aimed to clarify the mitochondrial protective effects of BGP-15 in a hypertension-induced heart failure model and “in vitro.” Spontaneously hypertensive rats (SHRs) received BGP-15 or placebo for 18 weeks. BGP-15 treatment preserved the normal mitochondrial ultrastructure and enhanced the mitochondrial fusion. Neonatal rat cardiomyocytes (NRCMs) were stressed by hydrogen-peroxide. BGP-15 treatment inhibited the mitochondrial fission processes, promoted mitochondrial fusion, maintained the integrity of the mitochondrial genome, and moreover enhanced the de novo biogenesis of the mitochondria. As a result of these effects, BGP-15 treatment also supports the maintenance of mitochondrial function through the preservation of the mitochondrial structure during hydrogen peroxide-induced oxidative stress as well as in an “in vivo” heart failure model. It offers the possibility, which pharmacological modulation of mitochondrial quality control under oxidative stress could be a novel therapeutic approach in heart failure.

Helix B Surface Peptide Protects against Acute Myocardial Ischemia-Reperfusion Injury via the RISK and SAFE Pathways in a Mouse Model

Cardiology ◽  
2016 ◽  
Vol 134 (2) ◽  
pp. 109-117 ◽  
Author(s):  
Peng Liu ◽  
Wei You ◽  
Lin Lin ◽  
Yongluan Lin ◽  
Xiuying Tang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Cardiomyocyte Apoptosis ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Gsk 3Β

Objective: This study explores the effects of helix B surface peptide (HBSP) on myocardial infarct size (IS), cardiac function, cardiomyocyte apoptosis and oxidative stress damage in mouse hearts subjected to myocardial ischemia-reperfusion injury (MIRI) and also the mechanisms underlying the effects. Method: Male adult mice were subjected to 45 min of ischemia followed by 2 h of reperfusion; 5 min before the reperfusion, they were treated with HBSP or vehicle. MIRI-induced IS, cardiomyocyte apoptosis and cardiac functional impairment were determined and compared. Western blot analysis was then conducted to elucidate the mechanism of HBSP after treatment. Results: HBSP administration before reperfusion significantly reduced the myocardial IS, decreased cardiomyocyte apoptosis, reduced the activities of superoxide dismutase and malondialdehyde and partially preserved heart function. As demonstrated by the Western blot analysis, HBSP after treatment upregulated Akt/GSK-3β/ERK and STAT-3 phosphorylation; these inhibitors, in turn, weakened the beneficial effects of HBSP. Conclusion: HBSP plays a protective role in MIRI in mice by inhibiting cardiomyocyte apoptosis, reducing the MIRI-induced IS, oxidative stress and improving the heart function after MIRI. The mechanism underlying these effects of HBSP is related to the activation of the RISK (reperfusion injury salvage kinase, Akt/GSK-3β/ERK) and SAFE (STAT-3) pathways.

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