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 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.

scholarly journals The proarrhythmic features of pathological cardiac hypertrophy in neonatal rat ventricular cardiomyocyte cultures

2020 ◽  
Vol 128 (3) ◽  
pp. 545-553
Author(s):  
Zeinab Neshati ◽  
Martin J. Schalij ◽  
Antoine A. F. de Vries
Keyword(s):  
Action Potential ◽  
Cardiac Hypertrophy ◽  
Action Potential Duration ◽  
In Vitro Model ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Control Group ◽  
Pathological Cardiac Hypertrophy ◽  
Vitro Model

Different factors may trigger arrhythmias in diseased hearts, including fibrosis, cardiomyocyte hypertrophy, hypoxia, and inflammation. This makes it difficult to establish the relative contribution of each of them to the occurrence of arrhythmias. Accordingly, in this study, we used an in vitro model of pathological cardiac hypertrophy (PCH) to investigate its proarrhythmic features and the underlying mechanisms independent of fibrosis or other PCH-related processes. Neonatal rat ventricular cardiomyocyte (nr-vCMC) monolayers were treated with phorbol 12-myristate 13-acetate (PMA) to create an in vitro model of PCH. The electrophysiological properties of PMA-treated and control monolayers were analyzed by optical mapping at day 9 of culture. PMA treatment led to a significant increase in cell size and total protein content. It also caused a reduction in sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 level (32%) and an increase in natriuretic peptide A (42%) and α1-skeletal muscle actin (34%) levels, indicating that the hypertrophic response induced by PMA was, indeed, pathological in nature. PMA-treated monolayers showed increases in action potential duration (APD) and APD dispersion, and a decrease in conduction velocity (CV; APD30 of 306 ± 39 vs. 148 ± 18 ms, APD30 dispersion of 85 ± 19 vs. 22 ± 7 and CV of 10 ± 4 vs. 21 ± 2 cm/s in controls). Upon local 1-Hz stimulation, 53.6% of the PMA-treated cultures showed focal tachyarrhythmias based on triggered activity ( n = 82), while the control group showed 4.3% tachyarrhythmias ( n = 70). PMA-treated nr-vCMC cultures may, thus, represent a well-controllable in vitro model for testing new therapeutic interventions targeting specific aspects of hypertrophy-associated arrhythmias. NEW & NOTEWORTHY Phorbol 12-myristate 13-acetate (PMA) treatment of neonatal rat ventricular cardiomyocytes (nr-vCMCs) led to induction of many significant features of pathological cardiac hypertrophy (PCH), including action potential duration prolongation and dispersion, which provided enough time and depolarizing force for formation of early afterdepolarization (EAD)-induced focal tachyarrhythmias. PMA-treated nr-vCMCs represent a well-controllable in vitro model, which mostly resembles to moderate left ventricular hypertrophy (LVH) rather than severe LVH, in which generation of a reentry is the putative mechanism of its arrhythmias.

scholarly journals Lysosomal-Associated Protein Transmembrane 5 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy

2021 ◽  
Vol 8 ◽  
Author(s):  
Lu Gao ◽  
Sen Guo ◽  
Rui Long ◽  
Lili Xiao ◽  
Rui Yao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Ventricular Myocytes ◽  
Therapeutic Potential ◽  
Negative Regulator ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Pathological Cardiac Hypertrophy

Lysosomal-associated protein transmembrane 5 (LAPTM5) is mainly expressed in immune cells and has been reported to regulate inflammation, apoptosis and autophagy. Although LAPTM5 is expressed in the heart, whether LAPTM5 plays a role in regulating cardiac function remains unknown. Here, we show that the expression of LAPTM5 is dramatically decreased in murine hypertrophic hearts and isolated hypertrophic cardiomyocytes. In this study, we investigated the role of LAPTM5 in pathological cardiac hypertrophy and its possible mechanism. Our results show that LAPTM5 gene deletion significantly exacerbates cardiac remodeling, which can be demonstrated by reduced myocardial hypertrophy, fibrosis, ventricular dilation and preserved ejection function, whereas the opposite phenotype was observed in LAPTM5 overexpression mice. In line with the in vivo results, knockdown of LAPTM5 exaggerated angiotensin II-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes, whereas overexpression of LAPTM5 protected against angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, LAPTM5 directly bound to Rac1 and further inhibited MEK-ERK1/2 signaling, which ultimately regulated the development of cardiac hypertrophy. In addition, the antihypertrophic effect of LAPTM5 was largely blocked by constitutively active mutant Rac1 (G12V). In conclusion, our results suggest that LAPTM5 is involved in pathological cardiac hypertrophy and that targeting LAPTM5 has great therapeutic potential in the treatment of pathological cardiac hypertrophy.

scholarly journals Bakuchiol protects against pathological cardiac hypertrophy by blocking NF-κB signaling pathway

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Zheng Wang ◽  
Lu Gao ◽  
Lili Xiao ◽  
Lingyao Kong ◽  
Huiting Shi ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Oral Gavage ◽  
Aortic Banding ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy ◽  
First Time

Bakuchiol (Bak), a monoterpene phenol isolated from the seeds of Psoralea corylifolia, has been widely used to treat a large variety of diseases in both Indian and Chinese folkloric medicine. However, the effects of Bak on cardiac hypertrophy remain unclear. Therefore, the present study was designed to determine whether Bak could alleviate cardiac hypertrophy. Mice were subjected to aortic banding (AB) to induce cardiac hypertrophy model. Bak of 1 ml/100 g body weight was given by oral gavage once a day from 1 to 8 weeks after surgery. Our data demonstrated for the first time that Bak could attenuate pressure overload-induced cardiac hypertrophy and could attenuate fibrosis and the inflammatory response induced by AB. The results further revealed that the effect of Bak on cardiac hypertrophy was mediated by blocking the activation of the NF-κB signaling pathway. In vitro studies performed in neonatal rat cardiomyocytes further proved that the protective effect of Bak on cardiac hypertrophy is largely dependent on the NF-κB pathway. Based on our results, Bak shows profound potential for its application in the treatment of pathological cardiac hypertrophy, and we believe that Bak may be a promising therapeutic candidate to treat cardiac hypertrophy and heart failure.

Abstract 026: Role of Tank in the Regulation of Pathological Cardiac Hypertrophy

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Hongliang Li ◽  
Peng Zhang
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Adaptor Protein ◽  
Negative Regulator ◽  
Akt Inhibitor ◽  
Aortic Banding ◽  
Pathological Cardiac Hypertrophy

TRAF associated NF-κB activator (TANK) is adaptor protein which was identified as a negative regulator of TRAF-, TBK1- and IKKi-mediated signal transduction through its interaction with them. Besides its important roles in the regulation of immune response, it has been reported that TANK contributes to the development of autoimmune nephritis and osteoclastogenesis. However, its functions in cardiovascular diseases especially cardiac hypertrophy is largely unknown. In the present study, we interestingly observed that TNAK expression is increased by 240% in human hypertrophic cardiomyopathy(HCM)tissue and 320% in mouse hypertrophic heart after aortic banding (AB), indicating that TANK may be involved in the pathogenesis of this diseases. Subsequently, cardiac-specific TANK knockout (TANK-KO) and transgenic(TANK-TG)mice were generated and subjected to AB for 4 to 8 weeks. Our results demonstrated that TANK deficiency prevented against cardiac hypertrophy and fibrosis induced by pressure overload,as evidenced by that the cardiomyocytes enlargement and fibrosis formation was reduced by about 34% and 43% compared with WT mice, respectively. Conversely, TANK-TG mice showed an aggravated effect on cardiac hypertrophy in response to pressure overload with 36% and 47% increase of cardiomyocytes enlargement and fibrosis formation compared with non-transgenic mice. More importantly, in vitro experiments further revealed that TANK overexpression which was mediated by adenovirus in the cardiomyocytes dramatically increased the cell size and the expression of hypertrophic markers, whereas TANK knockdown had an opposite function. Mechanistically, we discovered that AKT signaling was activated (230%) in the hearts of TANK-TG mice, while being greatly reduced in TNAK-KO hearts after aortic banding. Moreover, blocking AKT/GSK3β signaling with a pharmacological AKT inhibitor reversed cardiac dysfunction of TANK-TG mice. Collectively, our data show that TNAK acts as a novel regulator of pathological cardiac hypertrophy and may be a promising therapeutic targets.

Antioxidant potential of thyme extract: alleviation of N-nitrosodiethylamine-induced oxidative stress

2008 ◽  
Vol 27 (3) ◽  
pp. 215-221 ◽  
Author(s):  
P Rana ◽  
G Soni
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
Test Group ◽  
Normal Diet ◽  
Lower Degree ◽  
Control Group ◽  
Albino Rats ◽  
Stress Induction ◽  
And Control

Protective role of thyme extract against N-nitrosodiethylamine (NDEA)-induced oxidative stress has been evaluated in albino rats. For this, one group of rats were fed diet supplemented with thyme extract (0.5%) and served as the test group, whereas animals of the other group fed on normal diet served as the control group. The rats were fed on respective diets for a period of 2 weeks after which stress was induced to half the animals of each group by i.p. administration of NDEA at 200 mg/kg body weight. Animals were killed 48 h post stress-induction period. Feed intake and body weight decreased significantly in both test and control groups, the effect being less in test group. Increase in osmotic fragility and in-vitro lipid peroxidation (LPO) on stress induction was of lower degree in the test group. NDEA toxicity was mainly reflected in liver as evidenced by increased activities of plasma aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. The effect was of lower degree in test group as compared with that in the control group. Increase in urea levels observed following NDEA administration was also of lower degree in test groups. Blood glutathione (GSH) levels increased more so in test group compared with control group on stress induction. The activities of superoxide dismutase (SOD), peroxidase (Px), and catalase (CAT) activities decreased significantly on stress induction in erythrocytes. LPO increased in all the tissues through varying degree, and the increase was appreciably of lower degree in test group. The activity of SOD increased significantly in both test and control group on stress induction, whereas activities of Px and CAT decreased following NDEA treatment, and the effects were of lower degree in test group. Thus, supplementation of diet with thyme extract can improve antioxygenic potential and hence help to prevent oxidative stress.

scholarly journals Sophoricoside ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Maomao Gao ◽  
Fengjiao Hu ◽  
Manli Hu ◽  
Yufeng Hu ◽  
Hongjie Shi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Protective Effects ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy ◽  
Compound C

Abstract Aim: The study aims to evaluate protective effects of sophoricoside (Sop) on cardiac hypertrophy. Meanwhile, the potential and significance of Sop should be broadened and it should be considered as an attractive drug for the treatment of pathological cardiac hypertrophy and heart failure. Methods: Using the phenylephrine (PE)-induced neonatal rat cardiomyocytes (NRCMs) enlargement model, the potent protection of Sop against cardiomyocytes enlargement was evaluated. The function of Sop was validated in mice received transverse aortic coarctation (TAC) or sham surgery. At 1 week after TAC surgery, mice were treated with Sop for the following 4 weeks, the hearts were harvested after echocardiography examination. Results: Our study revealed that Sop significantly mitigated TAC-induced heart dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, Sop treatment induced a remarkable activation of AMPK/mTORC1-autophagy cascade following sustained hypertrophic stimulation. Importantly, the protective effect of Sop was largely abolished by the AMPKα inhibitor Compound C, suggesting an AMPK activation-dependent manner of Sop function on suppressing pathological cardiac hypertrophy. Conclusion: Sop ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy. Hence, Sop might be an attractive candidate for the treatment of pathological cardiac hypertrophy and heart failure.

scholarly journals Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload

2021 ◽  
Vol 12 ◽  
Author(s):  
Nan Zhang ◽  
Hai-Han Liao ◽  
Hong Feng ◽  
Shan-Qi Mou ◽  
Wen-Jing Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Conditional Knockout ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Genetic Toxicity ◽  
And Oxidative Stress ◽  
Dependent Pathway

Objectives: Sestrin2 (Sesn2) has been demonstrated to be a cysteine sulfinyl reductase and protects cells from multiple stress insults, including hypoxia, endoplasmic reticulum stress, and oxidative stress. However, the roles and mechanisms of Sesn2 in pressure overload-induced mouse cardiac hypertrophy have not been clearly clarified. This study intended to investigate whether sestrin2 (Sesn2) overexpression could prevent pressure overload-induced cardiac hypertrophy via an AMPKα2 dependent pathway through conditional knockout of AMPKα2.Methods and results: Sesn2 expression was significantly increased in mice hearts at 2 and 4 weeks after aortic banding (AB) surgery, but decreased to 60–70% of the baseline at 8 weeks. Sesn2 overexpression (at 3, 6, and 9 folds) showed little cardiac genetic toxicity in transgenic mice. Cardiac dysfunctions induced by pressure overload were attenuated by cardiomyocyte-specific Sesn2 overexpression when measured by echocardiography and hemodynamic analysis. Results of HE and PSR staining showed that Sesn2 overexpression significantly alleviated cardiac hypertrophy and fibrosis in mice hearts induced by pressure overload. Meanwhile, adenovirus-mediated-Sesn2 overexpression markedly suppressed angiotensin II-induced neonatal rat cardiomyocyte hypertrophy in vitro. Mechanistically, Sesn2 overexpression increased AMPKα2 phosphorylation but inhibited mTORC1 phosphorylation. The cardiac protections of Sesn2 overexpression were also via regulating oxidative stress by enhancing Nrf2/HO-1 signaling, restoring SOD activity, and suppressing NADPH activity. Particularly, we first proved the vital role of AMPKα2 in the regulation of Sesn2 with AMPKα2 knockout (AMPKα2-/-) mice and Sesn2 transgenic mice crossed with AMPKα2-/-, since Sesn2 overexpression failed to improve cardiac function, inhibit cardiac hypertrophy and fibrosis, and attenuate oxidative stress after AMPKα2 knockout.Conclusion: This study uniquely revealed that Sesn2 overexpression showed little genetic toxicity in mice hearts and inhibited mTORC1 activation and oxidative stress to protect against pressure overload-induced cardiac hypertrophy in an AMPKα2 dependent pathway. Thus, interventions through promoting Sesn2 expression might be a potential strategy for treating pathological cardiac hypertrophy and heart failure.

scholarly journals TANK Promotes Pressure Overload Induced Cardiac Hypertrophy via Activating AKT Signaling Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Yanan Pang ◽  
Minglu Ma ◽  
Dong Wang ◽  
Xun Li ◽  
Li Jiang
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Knockout Mice ◽  
Pressure Overload ◽  
Akt Signaling ◽  
Control Group ◽  
Akt Inhibitor ◽  
Aortic Banding ◽  
Pathological Cardiac Hypertrophy

Background: TANK (TRAF family member associated NF-κB activator) acts as a member of scaffold proteins participated in the development of multiple diseases. However, its function in process of cardiac hypertrophy is still unknown.Methods and Results: In this study, we observed an increased expression of TANK in murine hypertrophic hearts after aortic banding, suggesting that TANK may be involved in the pathogenesis of cardiac hypertrophy. We generated cardiac-specific TANK knockout mice, and subsequently subjected to aortic banding for 4–8 weeks. TANK knockout mice showed attenuated cardiac hypertrophy and dysfunction compared to the control group. In contrast, cardiac-specific TANK transgenic mice showed opposite signs. Consistently, in vitro experiments revealed that TANK knockdown decreased the cell size and expression of hypertrophic markers. Mechanistically, AKT signaling was inhibited in TANK knockout mice, but activated in TANK transgenic mice after aortic banding. Blocking AKT signaling with a pharmacological AKT inhibitor alleviated the cardiac hypertrophy and dysfunction in TANK transgenic mice.Conclusions: Collectively, we identified TANK accelerates the progression of pathological cardiac hypertrophy and is a potential therapeutic target.

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