scholarly journals The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation

2019 ◽  
Vol 5 (5) ◽  
pp. eaau0495 ◽  
Author(s):  
Xin Xie ◽  
Hai-Lian Bi ◽  
Song Lai ◽  
Yun-Long Zhang ◽  
Nan Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Inflammatory Diseases ◽  
Pressure Overload ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Adequate Treatment ◽  
Hypertrophic Response ◽  
Pathological Cardiac Hypertrophy ◽  
Mediated Reduction ◽  
Expression And Activity

Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. The immunoproteasome is an inducible form of the proteasome that is intimately involved in inflammatory diseases. Here, we found that the expression and activity of immunoproteasome catalytic subunit β5i were significantly up-regulated in angiotensin II (Ang II)–treated cardiomyocytes and in the hypertrophic hearts. Knockout of β5i in cardiomyocytes and mice markedly attenuated the hypertrophic response, and this effect was aggravated by β5i overexpression in cardiomyocytes and transgenic mice. Mechanistically, β5i interacted with and promoted ATG5 degradation thereby leading to inhibition of autophagy and cardiac hypertrophy. Further, knockdown of ATG5 or inhibition of autophagy reversed the β5i knockout-mediated reduction of cardiomyocyte hypertrophy induced by Ang II or pressure overload. Together, this study identifies a novel role for β5i in the regulation of cardiac hypertrophy. The inhibition of β5i activity may provide a new therapeutic approach for hypertrophic diseases.

Abstract 266: Novel Sites of Angiotension II Type 1 Receptor are Identified for Direct Activation by Mechanical Stretch Independent of Angiotension II

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Hui Gong ◽  
Guoliang Jiang ◽  
Chunjie Yang ◽  
Shijun Wang ◽  
Zhidan Chen ◽  
...  
Keyword(s):  
Mechanical Stress ◽  
Pressure Overload ◽  
Mechanical Stretch ◽  
Site Directed Mutagenesis ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Angiotension Ii ◽  
High Level

The angiotensin II type 1 receptor (AT1R) has a crucial role in cardiac hypertrophy induced by pressure overload. In the previous study, we found a novel mechanism for mechanical stress-induced AT1R activation without the involvement of Ang II. However, few reports focus on how AT1R senses mechanical stress and translates it into biochemical signals inside the cells to induce cardiomyocyte hypertrophy. Here, we constructed different site-directed mutagenesis of AT1R and transfected them to COS7 cells and ATG–/– (Angiotensinogen knockout) cardiomyocytes, respectively, to observe the activation of downstream signaling to identify functional site of AT1R. The results showed AT1R-WT, AT1R-K199Q, AT1R-L212F,AT1R-Q257A and AT1R-C289A plasmids or adenovirus were overexpressed at high level in plasma membrane of COS7 or cardiomyocytes respectively. There was no obvious difference in subcellular expression of wt-AT1R and all the mut-AT1Rs. The further study revealed that Ang II-induced-phosphorylation of ERK, Jak2 and the redistribution of Gαq11 were dramatically decreased in COS7 cells expressing AT1R-K199Q or AT1R-Q257A, while these effects induced by mechanical stretch were greatly suppressed in COS7 cells expressing AT1R-L212F,AT1R-Q257A or AT1R-C289A compared to these in COS7 cells expressing AT1R-WT. We then transfected the adenovirus of wt-AT1R or different mut-AT1Rs to ATG–/– cardiomyocytes to exclude the influence of endogenous Ang II. The results were consistent with these results in COS7 cells. Moreover, ATG–/– cardiomyocytes overexpressing AT1R-K199Q or AT1R-Q257A parlty abolished hypertrophic response induce by Ang II, while the cardiomyocytes overexpressing AT1R-L212F,AT1R-Q257A or AT1R-C289A greatly inhibited the hypertrophic response induced by mechanical stretch. The present study indicated that Leu212, Gln257 and Cys289 are critical sites for AT1R activation by mechanical stretch without Ang II but Lys199 and Gln257 play important role in AT1R activation with Ang II.

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.

Abstract P235: Balancing Truss Expression Paves a Way for Cardiac Hypertrophy Therapy

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Hongliang Li ◽  
Xiao-Jing Zhang ◽  
Ke-Qiong Deng
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Negative Regulator ◽  
Scaffolding Protein ◽  
Dependent Manner ◽  
Ang Ii ◽  
Pathological Cardiac Hypertrophy

Pathological cardiac hypertrophy, which is always accompanied by cardiac fibrosis and the resultant cardiac dysfunction, leads to hear failure and even sudden death. The TNF-receptor ubiquitous signaling and scaffolding protein (TRUSS) that is enriched in the heart has been identified as a negative regulator of cancer. However, the role of TRUSS in cardiac remodeling is unknown. Here, we aimed to investigate the potential participation of TRUSS in cardiac hypertrophy and the molecular events by which TRUSS regulates this pathological condition. The pathological cardiac hypertrophy model was established by pressure overload in vivo and Ang II stimulation in vitro . We observed that the expression level of TRUSS was dramatically increased in the heart and in primary cardiomyocytes upon pro-hypertrophic stimuli. To illustrate the functional role of TRUSS in cardiac remodeling, the cardiac specific knockout (KO) or transgenic (TG) mice were employed. After aortic binding (AB) for 4 weeks, TRUSS deficiency conferred significant resistance to pressure overload via significantly inhibiting cardiomyocytes enlargement and fibrosis formation by about 37% and 46%, respectively, whereas dramatically exacerbated hypertrophy, fibrosis, and cardiac dysfunction were shown in TRUSS-TG mice compared to their littermate controls. Mechanistically, TRUSS can directly bind to JNK, a well-known pro-hypertrophic factor, and activate its downstream pathway. Further investigations indicated that the aggravated effect of TRUSS on cardiac hypertrophy can be almost completely reversed by a specific JNK inhibitor, SP600125, indicating a JNK-dependent manner of TRUSS-regulated cardiac hypertrophy. The directly exacerbated function of TRUSS in cardiomyocytes and the JNK-dependent mechanisms were further validated in primary cardiomyocytes that treated with Ang II after infection with AdshTRUSS or AdTRUSS. Notably, the increased protein and mRNA expression of TRUSS was also observed in heart samples from patients with hypertrophic cardiac myopathy. In conclusion, TRUSS functions as a positive regulator of pathological cardiac hypertrophy, suggesting a promising therapeutic approach for the hypertrophy related heart diseases by balancing TRUSS expression.

scholarly journals Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes

2021 ◽  
Vol 8 ◽  
Author(s):  
Ran Xu ◽  
Le Kang ◽  
Siang Wei ◽  
Chunjie Yang ◽  
Yuanfeng Fu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Marker Genes ◽  
Autophagic Flux ◽  
Ang Ii ◽  
Neonatal Cardiomyocytes ◽  
Primary Mouse

Pathological cardiac hypertrophy, the adaptive response of the myocardium to various pathological stimuli, is one of the primary predictors and predisposing factors of heart failure. However, its molecular mechanisms underlying pathogenesis remain poorly understood. Here, we studied the function of Samm50 in mitophagy during Ang II-induced cardiomyocyte hypertrophy via lentiviruses mediated knockdown and overexpression of Samm50 protein. We first found that Samm50 is a key positive regulator of cardiac hypertrophy, for western blot and real-time quantitative PCR detection revealed Samm50 was downregulated both in pressure-overload-induced hypertrophic hearts and Ang II-induced cardiomyocyte hypertrophy. Then, Samm50 overexpression exhibits enhanced induction of cardiac hypertrophy marker genes and cell enlargement in primary mouse cardiomyocytes by qPCR and immunofluorescence analysis, respectively. Meanwhile, Samm50 remarkably reduced Ang II-induced autophagy as indicated by decreased mitophagy protein levels and autophagic flux, whereas the opposite phenotype was observed in Samm50 knockdown cardiomyocytes. However, the protective role of Samm50 deficiency against cardiac hypertrophy was abolished by inhibiting mitophagy through Vps34 inhibitor or Pink1 knockdown. Moreover, we further demonstrated that Samm50 interacted with Pink1 and stimulated the accumulation of Parkin on mitochondria to initiate mitophagy by co-immunoprecipitation analysis and immunofluorescence. Thus, these results suggest that Samm50 regulates Pink1-Parkin-mediated mitophagy to promote cardiac hypertrophy, and targeting mitophagy may provide new insights into the treatment of 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.

FNDC5/Irisin inhibits pathological cardiac hypertrophy

2019 ◽  
Vol 133 (5) ◽  
pp. 611-627 ◽  
Author(s):  
Qing Yu ◽  
Wenxin Kou ◽  
Xu Xu ◽  
Shunping Zhou ◽  
Peipei Luan ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Pressure Overload ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Pathological Cardiac Hypertrophy ◽  
Adam Family ◽  
A Disintegrin And Metalloproteinase

Abstract Cardiac hypertrophy is a common pathophysiological process in various cardiovascular diseases, which still has no effective therapies. Irisin is a novel myokine mainly secreted by skeletal muscle and is believed to be involved in the regulation of energy metabolism. In the present study, we found that irisin expression was elevated in hypertrophic murine hearts and serum. Moreover, angiotension II-induced cardiomyocyte hypertrophy was attenuated after irisin administration and aggravated after irisin knockdown in vitro. Next, we generated transverse aortic constriction (TAC)-induced cardiac hypertrophy murine model and found that cardiac hypertrophy and fibrosis were significantly attenuated with improved cardiac function assessed by echocardiography after irisin treatment. Mechanistically, we demonstrated that FNDC5 was cleaved into irisin, at least partially, in a disintegrin and metalloproteinase (ADAM) family-dependent manner. ADAM10 was the candidate enzyme responsible for the cleavage. Further, we found irisin treatment activated AMPK and subsequently inhibited activation of mTOR. AMPK inhibition ablated the protective role of irisin administration. In conclusion, we find irisin is secreted in an ADAM family-dependent manner, and irisin treatment improves cardiac function and attenuates pressure overload-induced cardiac hypertrophy and fibrosis mainly through regulating AMPK-mTOR signaling.

scholarly journals Novel Therapeutic Effects of Pterosin B on Ang II-Induced Cardiomyocyte Hypertrophy

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5279
Author(s):  
Chang Youn Lee ◽  
Han Ki Park ◽  
Bok-Sim Lee ◽  
Seongtae Jeong ◽  
Sung-Ae Hyun ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Therapeutic Effects ◽  
Ang Ii ◽  
Pathological Cardiac Hypertrophy ◽  
Glycation End Products ◽  
Abnormal Increase

Pathological cardiac hypertrophy is characterized by an abnormal increase in cardiac muscle mass in the left ventricle, resulting in cardiac dysfunction. Although various therapeutic approaches are being continuously developed for heart failure, several studies have suggested natural compounds as novel potential strategies. Considering relevant compounds, we investigated a new role for Pterosin B for which the potential life-affecting biological and therapeutic effects on cardiomyocyte hypertrophy are not fully known. Thus, we investigated whether Pterosin B can regulate cardiomyocyte hypertrophy induced by angiotensin II (Ang II) using H9c2 cells. The antihypertrophic effect of Pterosin B was evaluated, and the results showed that it reduced hypertrophy-related gene expression, cell size, and protein synthesis. In addition, upon Ang II stimulation, Pterosin B attenuated the activation and expression of major receptors, Ang II type 1 receptor and a receptor for advanced glycation end products, by inhibiting the phosphorylation of PKC-ERK-NF-κB pathway signaling molecules. In addition, Pterosin B showed the ability to reduce excessive intracellular reactive oxygen species, critical mediators for cardiac hypertrophy upon Ang II exposure, by regulating the expression levels of NAD(P)H oxidase 2/4. Our results demonstrate the protective role of Pterosin B in cardiomyocyte hypertrophy, suggesting it is a potential therapeutic candidate.

scholarly journals Corosolic acid ameliorates cardiac hypertrophy via regulating autophagy

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Zhao-Peng Wang ◽  
Difei Shen ◽  
Yan Che ◽  
Ya-Ge Jin ◽  
Sha-Sha Wang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
In Vivo Studies ◽  
Cardiomyocyte Hypertrophy ◽  
H9c2 Cells ◽  
Hypertrophic Response ◽  
Post Surgery ◽  
Corosolic Acid

Abstract Aim: In this work, we explored the role of corosolic acid (CRA) during pressure overload-induced cardiac hypertrophy. Methods and results: Cardiac hypertrophy was induced in mice by aortic banding. Four weeks post-surgery, CRA-treated mice developed blunted cardiac hypertrophy, fibrosis, and dysfunction, and showed increased LC3 II and p-AMPK expression. In line with the in vivo studies, CRA also inhibited the hypertrophic response induced by PE stimulation accompanying with increased LC3 II and p-AMPK expression. It was also found that CRA blunted cardiomyocyte hypertrophy and promoted autophagy in Angiotensin II (Ang II)-treated H9c2 cells. Moreover, to further verify whether CRA inhibits cardiac hypertrophy by the activation of autophagy, blockade of autophagy was achieved by CQ (an inhibitor of the fusion between autophagosomes and lysosomes) or 3-MA (an inhibitor of autophagosome formation). It was found that autophagy inhibition counteracts the protective effect of CRA on cardiac hypertrophy. Interestingly, AMPK knockdown with AMPKα2 siRNA-counteracted LC3 II expression increase and the hypertrophic response inhibition caused by CRA in PE-treated H9c2 cells. Conclusion: These results suggest that CRA may protect against cardiac hypertrophy through regulating AMPK-dependent autophagy.

Abstract 51: Thymosin β4 Targets Wisp1 to Protect Cardiomyocytes in AngII- induced Cardiac Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sudhiranjan Gupta ◽  
Li Li ◽  
Rakesh Guleria ◽  
Kenneth M Baker
Keyword(s):  
Cardiac Hypertrophy ◽  
Fluorescent Microscopy ◽  
Marker Genes ◽  
Protective Mechanism ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Antiapoptotic Proteins ◽  
Neonatal Cardiomyocytes ◽  
Cell Proliferation And Differentiation ◽  
Pre Treatment

Background: Thymosin beta-4 (Tβ4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. However, the role of Tβ4 in cardiomyocytes hypertrophy is currently unknown. The purpose of this study is to dissect the cardio-protective mechanism of Tβ4 in Ang II induced cardiac hypertrophy. Methods: Rat neonatal cardiomyocytes with or without Tβ4 pretreatment were stimulated with Ang II and expression of cell sizes, hypertrophy marker genes and Wnt signaling components was evaluated by quantitative real-time PCR, western blotting and fluorescent microscopy. Selected target gene Wisp-1 was either overexpressed or silenced by siRNA transfections in neonatal cardiomyocytes and effect of Tβ4 in Ang II-induced cardiac hypertrophy was evaluated. Results: Pre-treatment of Tβ4 resulted in reduction of cell sizes, hypertrophy marker genes and WNT-associated gene expression and levels induced by Ang II in cardiomyocytes. Tβ4 pretreatment also resulted in an increase in the expression of antiapoptotic proteins and reduction of Bax/BCl 2 ratio in the cardiomyocytes. Wisp-1 overexpression promotes cardiac hypertrophy and was reversed by pretreatment with Tβ4. Knocking down of Wisp1 partly rescue the cells from hypertrophic response after Tβ4 treatment. Conclusion: This is the first report that demonstrates the effect of Tβ4 on cardiomyocytes hypertrophy and its capability to selectively target Wisp-1 in neonatal cardiomyocytes thus preventing cell death, thereby, protecting the myocardium. Wisp-1 promotes the cardiac hypertrophy which was prevented by Tβ4 treatment.

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.

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