Reducing Oxidative Stress and Manipulating Molecular Signaling Events Using Resveratrol as a Therapy for Pathological Cardiac Hypertrophy

2013 ◽  
pp. 227-254
Author(s):  
Shereen M. Hamza ◽  
Miranda M. Sung ◽  
Jason R. B. Dyck
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Molecular Signaling ◽  
Pathological Cardiac Hypertrophy ◽  
Signaling Events

scholarly journals Role of CyPA in cardiac hypertrophy and remodeling

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Mengfei Cao ◽  
Wei Yuan ◽  
Meiling Peng ◽  
Ziqi Mao ◽  
Qianru Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Cardiomyocyte Hypertrophy ◽  
Pathological Cardiac Hypertrophy ◽  
Complex Process

Abstract Pathological cardiac hypertrophy is a complex process and eventually develops into heart failure, in which the heart responds to various intrinsic or external stress, involving increased interstitial fibrosis, cell death and cardiac dysfunction. Studies have shown that oxidative stress is an important mechanism for this maladaptation. Cyclophilin A (CyPA) is a member of the cyclophilin (CyPs) family. Many cells secrete CyPA to the outside of the cells in response to oxidative stress. CyPA from blood vessels and the heart itself participate in a variety of signaling pathways to regulate the production of reactive oxygen species (ROS) and mediate inflammation, promote cardiomyocyte hypertrophy and proliferation of cardiac fibroblasts, stimulate endothelial injury and vascular smooth muscle hyperplasia, and promote the dissolution of extracellular matrix (ECM) by activating matrix metalloproteinases (MMPs). The events triggered by CyPA cause a decline of diastolic and systolic function and finally lead to the occurrence of heart failure. This article aims to introduce the role and mechanism of CyPA in cardiac hypertrophy and remodeling, and highlights its potential role as a disease biomarker and therapeutic target.

Analysis of Drosophila cardiac hypertrophy by micro-computerized tomography for genetic dissection of heart growth mechanisms

2021 ◽  
Author(s):  
Courtney E Petersen ◽  
Benjamin A Tripoli ◽  
Todd A Schoborg ◽  
Jeremy T Smyth
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Computerized Tomography ◽  
Genetic Model ◽  
Genetic Dissection ◽  
Molecular Signaling ◽  
Pathological Cardiac Hypertrophy ◽  
Underlying Mechanisms ◽  
Microct Analysis ◽  
Constitutively Active

Heart failure is often preceded by pathological cardiac hypertrophy, a thickening of the heart musculature driven by complex gene regulatory and signaling processes. The Drosophila heart has great potential as a genetic model for deciphering the underlying mechanisms of cardiac hypertrophy. However, current methods for evaluating hypertrophy of the Drosophila heart are laborious and difficult to carry out reproducibly. Here we demonstrate that micro-computerized tomography (microCT) is an accessible, highly reproducible method for non-destructive, quantitative analysis of Drosophila heart morphology and size. To validate our microCT approach for analyzing Drosophila cardiac hypertrophy, we show that expression of constitutively active Ras (Ras85DV12), previously shown to cause hypertrophy of the fly heart, results in significant thickening of both adult and larval heart walls when measured from microCT images. We then show using microCT analysis that genetic upregulation of store-operated Ca2+ entry (SOCE) driven by expression of constitutively active Stim (StimCA) or Orai (OraiCA) proteins also results in significant hypertrophy of the Drosophila heart, through a process that specifically depends on Orai Ca2+ influx channels. Intravital imaging of heart contractility revealed significantly reduced end diastolic and systolic dimensions in StimCA and OraiCA expressing hearts, consistent with the hypertrophic phenotype. These results demonstrate that increased SOCE activity is an important driver of hypertrophic cardiomyocyte growth, and demonstrate how microCT analysis combined with tractable genetic tools in Drosophila can be used to delineate molecular signaling processes that underlie cardiac hypertrophy and heart failure.

Abstract 434: Sirt4 Accelerates Ang II-induced Pathological Cardiac Hypertrophy by Inhibiting Mnsod Activity

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Depei Liu ◽  
Yu-Xuan Luo ◽  
Xiaoqiang Tang ◽  
Xi-Zhou An ◽  
Xue-Min Xie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Manganese Superoxide Dismutase ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy

Aims: Oxidative stress contributes to the development of cardiac hypertrophy and heart failure. One of the mitochondrial sirtuins, Sirt4, is highly expressed in the heart, but its function remains unknown. The aim of the present study was to investigate the role of Sirt4 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism by which Sirt4 regulates mitochondrial oxidative stress. Methods and results: Male C57BL/6 Sirt4 knockout mice, transgenic mice exhibiting cardiac-specific overexpression of Sirt4 (Sirt4-Tg) and their respective controls were treated with angiotensin II (Ang II). At 4 weeks, hypertrophic growth of cardiomyocytes, fibrosis and cardiac function were analyzed. Sirt4 deficiency conferred resistance to Ang II infusion by significantly suppressing hypertrophic growth, and the deposition of fibrosis. In Sirt4-Tg mice, aggravated hypertrophy and reduced cardiac function were observed compared with non-transgenic mice following Ang II treatment. Mechanistically, Sirt4 inhibited the binding of manganese superoxide dismutase (MnSOD) to Sirt3, another member of the mitochondrial sirtuins, and increased MnSOD acetylation levels to reduce its activity, resulting in elevated reactive oxygen species (ROS) accumulation upon Ang II stimulation. Furthermore, inhibition of ROS with MnTBAP, a mimetic of SOD, blocked the Sirt4-mediated aggravation of the hypertrophic response in Ang II-treated Sirt4-Tg mice. Conclusions: Sirt4 promotes hypertrophic growth and cardiac dysfunction by increasing ROS levels upon pathological stimulation. These findings reveal a role of Sirt4 in pathological cardiac hypertrophy, providing a new potential therapeutic strategy for this disease.

scholarly journals Novel PGC-1α/ATF5 Axis Partly Activates UPRmt and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy

2020 ◽  
Vol 2020 ◽  
pp. 1-21
Author(s):  
Bing Zhang ◽  
Yanzhen Tan ◽  
Zhengbin Zhang ◽  
Pan Feng ◽  
Wenyuan Ding ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Test Group ◽  
Neonatal Rat ◽  
Activation Mechanism ◽  
Cardiomyocyte Hypertrophy ◽  
Control Group ◽  
Pathological Cardiac Hypertrophy

Mitochondrial unfolding protein response (UPRmt) effectively resists the pathological cardiac hypertrophy and improves the mitochondrial function. However, the specific activation mechanism and drugs that can effectively activate UPRmt in the cardiac muscle are yet to be elucidated. The aim of this study was to determine the regulation role of UPRmt on preventing pathological cardiac hypertrophy by tetrahydrocurcumin (THC) and explore its underlying molecular mechanism. Male C57BL/6J wild-type (WT) mice were divided into a control group and subjected to sham treatment for 4 weeks, and a test group which was subjected to transverse aortic constriction (TAC) surgery. Animals in the control and test group were orally administered THC (50 mg/kg) for 4 weeks after TAC procedure; an equivalent amount of saline was orally administered in the control sham-treated group and the TAC group. Subsequently, oxidative stress and UPRmt markers were assessed in these mice, and cardiac hypertrophy, fibrosis, and cardiac function were tested. Small interfering RNA (siRNA) targeting proliferator-activated receptor-gamma coactivator (PGC)-1α and activating transcription factor 5 (ATF5) were used to determine the UPRmt activation mechanism. THC supplement partly upregulated UPRmt effectors and inhibited TAC-induced oxidative stress compared with TAC-operated WT mice, thereby substantially attenuating contractile dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, PGC-1α knockdown blunted the UPRmt activation and the cardioprotective role of THC. The interaction between PGC-1α and ATF5 was tested in neonatal rat cardiac myocytes under normal conditions. The results showed that PGC-1α was an upstream effector of ATF5 and partly activated UPRmt. In vitro, phenylephrine- (PE-) induced cardiomyocyte hypertrophy caused ATF5 upregulating rather than downregulating corresponding to the downregulation of PGC-1α. The PGC-1α/ATF5 axis mediated the UPRmt activation and stress-resistance role of THC in vitro. Collectively, the present study provides the first evidence that PGC-1 and ATF5 can form a signaling axis to partly activate UPRmt that mediates the cardioprotective role of THC in pathological cardiac hypertrophy.

scholarly journals LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Shi Peng ◽  
Xiao-feng Lu ◽  
Yi-ding Qi ◽  
Jing Li ◽  
Juan Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Aims. We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. Methods. In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. Results. Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. Conclusions. LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.

scholarly journals A novel micro-computerized tomography method reveals Drosophila cardiac hypertrophy caused by upregulated store-operated calcium entry

2021 ◽  
Author(s):  
Courtney E Petersen ◽  
Todd A Schoborg ◽  
Jeremy T Smyth
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Computerized Tomography ◽  
Genetic Model ◽  
Molecular Signaling ◽  
Pathological Cardiac Hypertrophy ◽  
Store Operated Calcium Entry ◽  
Underlying Mechanisms ◽  
Microct Analysis ◽  
Constitutively Active

ABSTRACTHeart failure is often preceded by pathological cardiac hypertrophy, a thickening of the heart musculature driven by complex gene regulatory and signaling processes. The Drosophila heart has great potential as a genetic model for deciphering the mechanisms that underlie cardiac hypertrophy. However, current methods for evaluating hypertrophy of the Drosophila heart are laborious and difficult to carry out reproducibly. Here we demonstrate that micro-computerized tomography (microCT) is an accessible, highly reproducible method for non-destructive, quantitative analysis of the morphology and size of the Drosophila heart. To validate our microCT approach for analyzing Drosophila cardiac hypertrophy, we show that expression of constitutively active Ras (Ras85DV12), previously shown to cause hypertrophy of the fly heart, results in significant thickening of both adult and larval heart walls when measured from microCT images. We then show using microCT analysis that genetic upregulation of store-operated Ca2+ entry (SOCE) driven by expression of constitutively active Stim (StimCA) or Orai (OraiCA) proteins also results in significant hypertrophy of the Drosophila heart, through a process that specifically depends on Ca2+ influx through Orai channels. Importantly, dysregulation of Ca2+ homeostasis in cardiomyocytes is a major driver of cardiac hypertrophy, but the underlying mechanisms are unclear. These results demonstrate that increased SOCE activity is an important driver of hypertrophic cardiomyocyte growth, and demonstrate how microCT analysis combined with tractable genetic tools in Drosophila can be used to delineate molecular signaling processes that underlie cardiac hypertrophy and heart failure.

Diazoxide Modulates Cardiac Hypertrophy by Targeting H2O2 Generation and Mitochondrial Superoxide Dismutase Activity

2020 ◽  
Vol 13 (1) ◽  
pp. 76-83
Author(s):  
Aline Maria Brito Lucas ◽  
Joana Varlla de Lacerda Alexandre ◽  
Maria Thalyne Silva Araújo ◽  
Cicera Edna Barbosa David ◽  
Yuana Ivia Ponte Viana ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Cardiac Hypertrophy ◽  
Superoxide Dismutase Activity ◽  
Heart Weight ◽  
Pharmacological Intervention ◽  
Wall Thickening ◽  
H2o2 Production ◽  
Mitochondrial Superoxide ◽  
Mitochondrial Superoxide Dismutase

Background: Cardiac hypertrophy involves marked wall thickening or chamber enlargement. If sustained, this condition will lead to dysfunctional mitochondria and oxidative stress. Mitochondria have ATP-sensitive K+ channels (mitoKATP) in the inner membrane that modulate the redox status of the cell. Objective: We investigated the in vivo effects of mitoKATP opening on oxidative stress in isoproterenol- induced cardiac hypertrophy. Methods: Cardiac hypertrophy was induced in Swiss mice treated intraperitoneally with isoproterenol (ISO - 30 mg/kg/day) for 8 days. From day 4, diazoxide (DZX - 5 mg/kg/day) was used in order to open mitoKATP (a clinically relevant therapy scheme) and 5-hydroxydecanoate (5HD - 5 mg/kg/day) or glibenclamide (GLI - 3 mg/kg/day) were used as mitoKATP blockers. Results: Isoproterenol-treated mice had elevated heart weight/tibia length ratios (HW/TL). Additionally, hypertrophic hearts had elevated levels of carbonylated proteins and Thiobarbituric Acid Reactive Substances (TBARS), markers of protein and lipid oxidation. In contrast, mitoKATP opening with DZX avoided ISO effects on gross hypertrophic markers (HW/TL), carbonylated proteins and TBARS, in a manner reversed by 5HD and GLI. Moreover, DZX improved mitochondrial superoxide dismutase activity. This effect was also blocked by 5HD and GLI. Additionally, ex vivo treatment of isoproterenol- induced hypertrophic cardiac tissue with DZX decreased H2O2 production in a manner sensitive to 5HD, indicating that this drug also acutely avoids oxidative stress. Conclusion: Our results suggest that diazoxide blocks oxidative stress and reverses cardiac hypertrophy. This pharmacological intervention could be a potential therapeutic strategy to prevent oxidative stress associated with cardiac hypertrophy.

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