Cullin-associated and neddylation-dissociated 1 protein (CAND1) governs cardiac hypertrophy and heart failure partially through regulating calcineurin degradation

2021 ◽  
Author(s):  
Zhenwei Pan ◽  
Xingda Li ◽  
Yang Zhang ◽  
Yue Zhao ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Protein Level ◽  
Substrate Protein ◽  
Pathological Cardiac Hypertrophy ◽  
Promising Therapeutic Target ◽  
Specific Proteins ◽  
Related Proteins

Abstract Pathological cardiac hypertrophy is a process characterized by significant disturbance of protein turnover. Cullin-associated and Neddylation-dissociated 1 (CAND1) acts as a coordinator to modulate substrate protein degradation by promoting the formation of specific cullin-based ubiquitin ligase 3 complex in response to the accumulation of specific proteins, which thereby maintains the normal protein homeostasis. However, whether CAND1 titrates the degradation of hypertrophic related proteins and manipulates cardiac hypertrophy remains unknown. In this study, we found that the protein level of CAND1 was increased in the heart tissues from heart failure (HF) patients and TAC mice. CAND1-KO+/- aggravated TAC-induced cardiac hypertrophic phenotypes; in contrast, CAND1-Tg attenuated the maladaptive cardiac remodeling. At the protein level, CAND1 overexpression downregulated, whereas CAND1-KO+/- or knockdown upregulated the expression of calcineurin, a critical pro-hypertrophic protein at both in vivo and in vitro conditions. Mechanistically, CAND1 overexpression favored, whilst CAND1 knockdown blocked the assembly of Cul1/atrogin1/calcineurin complex, an E3 that renders the ubiquitination and degradation of calcineurin. It turned out that calcineurin ubiquitination was suppressed by CAND1 knockdown, but enhanced by CAND1 overexpression. In addition, overexpression of truncated calcineurin that cannot be recognized by atrogin1 abrogated the antihypertrophic effects of CAND1. Notably, CAND1 deficiency-induced hypertrophic phenotypes were partially rescued by knockdown of calcineurin, and application of exogenous CAND1 prevented TAC-induced cardiac hypertrophy and heart failure. In conclusion, CAND1 exerts a protective effect against cardiac hypertrophy and heart failure partially by inducing the degradation of calcineurin. CAND1 represents a novel, promising therapeutic target for cardiac hypertrophy and heart failure. Keywords: CAND1; heart failure; calcineurin; ubiquitination; cullin1

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.

Abstract 420: Delineating the Caspase-dependent Targets and Signal Pathways That Promote Pathological Cardiac Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Charis Putinski ◽  
Mohammad Abdul-Ghani ◽  
Rebecca Stiles ◽  
Steve Brunette ◽  
Sarah A Dick ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pathological Process ◽  
Signal Pathways ◽  
Caspase Cleavage ◽  
Substrate Protein ◽  
Cell Death Pathway ◽  
Effector Caspase ◽  
The Impact

Although cardiac hypertrophy is initially an adaptive response, chronic stress on the heart is a maladaptive process that inevitably leads to end-stage heart failure. Interestingly, this pathological process is also characterized by cell behaviors associated with apoptosis. We previously demonstrated the essential role of the intrinsic cell death pathway during cardiac hypertrophy; however, the caspase-dependent pathways and cleavage targets remain elusive. To this aim, we evaluated a myocyte enhancer factor 2 (MEF2) transcription factor inhibitor, histone deacetylase 3 (HDAC3), and gelsolin as potential caspase cleavage substrates involved in the induction and/or maintenance of cardiac hypertrophy. In vitro cleavage assays were completed with effector caspase and recombinant substrate protein which demonstrated caspase-dependent cleavage. HDAC3 cleavage was observed during early stages of hypertrophy and reduced in the presence of a caspase inhibitor. Luciferase assays demonstrated that the transcriptional activity of MEF2 is dependent on intact caspase function suggesting caspase-directed HDAC3 cleavage may serve as a novel regulatory mechanism to alleviate MEF2 suppression to engage the hypertrophy gene expression program. Unlike HDAC3, caspase mediated gelsolin cleavage occurs at latter stages and is coincident with the cytoskeletal alterations that occur during this process. As gelsolin is a potent actin capping/severing enzyme, we hypothesize that caspase-mediated gelsolin activation acts as a key regulatory step in the structural rearrangements that allow for hypertrophy to occur. We have generated adenoviral vectors containing caspase cleavage mutants and cleaved forms of HDAC3 and gelsolin and will discuss the impact of these modified substrates on the hypertrophy process in vitro and in vivo. Collectively, this work suggests that caspase signalling acts to engage both the transcriptional program and cytoskeletal accommodations that characterize cardiac hypertrophy. Importantly, these observations suggest that identification of inhibitors that suppress caspase activity and/or activity of its cognate substrates may offer novel therapeutic targets to limit the development of pathological hypertrophy.

scholarly journals Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure

2017 ◽  
Vol 114 (45) ◽  
pp. 12033-12038 ◽  
Author(s):  
Iacopo Gesmundo ◽  
Michele Miragoli ◽  
Pierluigi Carullo ◽  
Letizia Trovato ◽  
Veronica Larcher ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Therapeutic Potential ◽  
Growth Hormone Releasing Hormone ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction

It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH2 attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cβ, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gαs and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy.

scholarly journals Myricetin Alleviates Pathological Cardiac Hypertrophy via TRAF6/TAK1/MAPK and Nrf2 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hai-han Liao ◽  
Nan Zhang ◽  
Yan-yan Meng ◽  
Hong Feng ◽  
Jing-jing Yang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Mapk Signaling ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Pathological Cardiac Hypertrophy ◽  
Pathological Hypertrophy ◽  
Nrf2 Signaling Pathway

Myricetin (Myr) is a common plant-derived polyphenol and is well recognized for its multiple activities including antioxidant, anti-inflammation, anticancer, and antidiabetes. Our previous studies indicated that Myr protected mouse heart from lipopolysaccharide and streptozocin-induced injuries. However, it remained to be unclear whether Myr could prevent mouse heart from pressure overload-induced pathological hypertrophy. Wild type (WT) and cardiac Nrf2 knockdown (Nrf2-KD) mice were subjected to aortic banding (AB) surgery and then administered with Myr (200 mg/kg/d) for 6 weeks. Myr significantly alleviated AB-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction in both WT and Nrf2-KD mice. Myr also inhibited phenylephrine- (PE-) induced neonatal rat cardiomyocyte (NRCM) hypertrophy and hypertrophic markers’ expression in vitro. Mechanically, Myr markedly increased Nrf2 activity, decreased NF-κB activity, and inhibited TAK1/p38/JNK1/2 MAPK signaling in WT mouse hearts. We further demonstrated that Myr could inhibit TAK1/p38/JNK1/2 signaling via inhibiting Traf6 ubiquitination and its interaction with TAK1 after Nrf2 knockdown in NRCM. These results strongly suggested that Myr could attenuate pressure overload-induced pathological hypertrophy in vivo and PE-induced NRCM hypertrophy via enhancing Nrf2 activity and inhibiting TAK1/P38/JNK1/2 phosphorylation by regulating Traf6 ubiquitination. Thus, Myr might be a potential strategy for therapy or adjuvant therapy for malignant cardiac hypertrophy.

scholarly journals Citri Reticulatae Pericarpium Alleviates Postmyocardial Infarction Heart Failure by Upregulating Pparγ Expression

2021 ◽  
Author(s):  
Mengli Chen ◽  
Hongyan Zhu ◽  
Qingqing Zhu ◽  
Xiaodong Wu ◽  
Yufei Zhou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Systolic Function ◽  
Tunel Staining ◽  
Mouse Heart ◽  
Coronary Artery Ligation ◽  
Traditional Chinese Herbal Medicine

Abstract PurposeHeart failure after myocardial infarction (MI) is the leading cause of death worldwide. Citri Reticulatae Pericarpium (CRP) is a traditional Chinese herbal medicine that has been used in the clinic for centuries. In this study, we aimed to investigate the roles of CRP in cardiac remodeling and heart failure after MI, as well as the molecular mechanisms involved.MethodsMale C57BL/6 mice aged 8 weeks were subjected to coronary artery ligation to mimic the clinical situation in vivo. Echocardiography was used to assess the systolic function of the mouse heart. Masson trichrome staining and Wheat germ agglutinin (WGA) staining were utilized to determine the fibrotic area and cross-sectional area of the mouse heart, respectively. Cardiomyocytes and fibroblasts were isolated from neonatal rats aged 0–3 days in vitro using enzyme digestion. TUNEL staining and EdU staining were performed to evaluate apoptosis and proliferation, respectively. Gene expression changes were analyzed by qRT–PCR, and protein expression changes were assessed by Western blotting.ResultsOur findings revealed that CRP attenuated cardiac hypertrophy, fibrosis and apoptosis and alleviated heart failure after MI in vivo. Furthermore, CRP mitigated cardiomyocyte apoptosis and fibroblast proliferation and differentiation into myofibroblasts. In addition, the PPARγ inhibitor T0070907 completely abolished the abovementioned beneficial effects of CRP, and the PPARγ activator rosiglitazone failed to further ameliorate cardiac apoptosis and fibrosis in vitro.ConclusionCRP alleviates cardiac hypertrophy, fibrosis, and apoptosis and can ameliorate heart failure after MI via activation of PPARγ.

scholarly journals Hispidulin Attenuates Cardiac Hypertrophy by Improving Mitochondrial Dysfunction

2020 ◽  
Vol 7 ◽  
Author(s):  
Yan Wang ◽  
Zengshuo Xie ◽  
Nan Jiang ◽  
Zexuan Wu ◽  
Ruicong Xue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Mitochondrial Function ◽  
Specific Inhibitor ◽  
Cardiomyocyte Hypertrophy ◽  
Mitochondrial Morphology ◽  
Protective Effects

Cardiac hypertrophy is a pathophysiological response to harmful stimuli. The continued presence of cardiac hypertrophy will ultimately develop into heart failure. The mitochondrion is the primary organelle of energy production, and its dysfunction plays a crucial role in the progressive development of heart failure from cardiac hypertrophy. Hispidulin, a natural flavonoid, has been substantiated to improve energy metabolism and inhibit oxidative stress. However, how hispidulin regulates cardiac hypertrophy and its underlying mechanism remains unknown. We found that hispidulin significantly inhibited pressure overload-induced cardiac hypertrophy and improved cardiac function in vivo and blocked phenylephrine (PE)-induced cardiomyocyte hypertrophy in vitro. We further proved that hispidulin remarkably improved mitochondrial function, manifested by increased electron transport chain (ETC) subunits expression, elevated ATP production, increased oxygen consumption rates (OCR), normalized mitochondrial morphology, and reduced oxidative stress. Furthermore, we discovered that Sirt1, a well-recognized regulator of mitochondrial function, might be a target of hispidulin, as evidenced by its upregulation after hispidulin treatment. Cotreatment with EX527 (a Sirt1-specific inhibitor) and hispidulin nearly completely abolished the antihypertrophic and protective effects of hispidulin on mitochondrial function, providing further evidence that Sirt1 could be the pivotal downstream effector of hispidulin in regulating cardiac hypertrophy.

scholarly journals STING protects against cardiac dysfunction and remodelling by blocking autophagy

2021 ◽  
Author(s):  
Rui Xiong ◽  
Ning Li ◽  
Wei Wang ◽  
Bo Wang ◽  
Wenyang Jiang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Protein Expression ◽  
Cardiac Fibroblasts ◽  
Cardiac Remodelling ◽  
Ang Ii ◽  
Mrna And Protein Expression

Abstract Background Heart failure, which is characterized by cardiac remodelling, is one of the most common chronic diseases in the aged. Stimulator of interferon genes (STING) acts as an indispensable molecule modulating immune response and inflammation in many diseases. However, the effects of STING on cardiomyopathy, especially cardiac remodelling are still largely unknown. This study was designed to investigate whether STING could affect cardiac remodelling and to explore the potential mechanisms. Methods In vivo, aortic binding (AB) surgery was performed to construct the mice model of cardiac remodelling. A DNA microinjection system was used to trigger STING overexpression in mice. The STING mRNA and protein expression levels in mice heart were measured, and the cardiac hypertrophy, fibrosis, inflammation and cardiac function were also evaluated. In vitro, cardiomyocytes stimulated by Ang II and cardiac fibroblasts stimulated by TGF-β to performed to further study effects of STING on cardiac hypertrophy and fibroblast. In terms of mechanisms, the level of autophagy was detected in mice challenged with AB. Rapamycin, a canonical autophagy inducer, intraperitoneal injected into mice to study possible potential pathway. Results In vivo, the STING mRNA and protein expression levels in mice heart challenged with AB for 6 weeks were significantly increased. STING overexpression significantly mitigated cardiac hypertrophy, fibrosis and inflammation, apart from improving cardiac function. In vitro, experiments further disclosed that STING overexpression in cardiomyocytes induced by Ang II significantly inhibited the level of cardiomyocyte cross-section area and the ANP mRNA. Meanwhile, TGF-β-induced the increase of α-SMA content and collagen synthesis in cardiac fibroblasts could be also blocked by STING overexpression. In terms of mechanisms, mice challenged with AB showed higher level of autophagy compared with the normal mice. However, STING overexpression could reverse the activation of autophagy triggered by AB. Rapamycin, a canonical autophagy inducer, offset the cardioprotective effects of STING in mice challenged with AB. Finally, further experiments unveiled that STING may inhibit autophagy by phosphorylating ULK1 on serine757. Conclusions STING may prevent cardiac remodelling induced by pressure overload by inhibiting autophagy, which could be a promising therapeutic target in heart failure.

Dual specific phosphatase 12 ameliorates cardiac hypertrophy in response to pressure overload

2016 ◽  
Vol 131 (2) ◽  
pp. 141-154 ◽  
Author(s):  
Wei-ming Li ◽  
Yi-fan Zhao ◽  
Guo-fu Zhu ◽  
Wen-hui Peng ◽  
Meng-yun Zhu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Contractile Function ◽  
Pressure Overload ◽  
Loss Of Function ◽  
Pathological Cardiac Hypertrophy ◽  
Dual Specific Phosphatase

Pathological cardiac hypertrophy is an independent risk factor of heart failure. However, we still lack effective methods to reverse cardiac hypertrophy. DUSP12 is a member of the dual specific phosphatase (DUSP) family, which is characterized by its DUSP activity to dephosphorylate both tyrosine and serine/threonine residues on one substrate. Some DUSPs have been identified as being involved in the regulation of cardiac hypertrophy. However, the role of DUSP12 during pathological cardiac hypertrophy is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in hypertrophic hearts and cardiomyocytes. Using a genetic loss-of-function murine model, we demonstrated that DUSP12 deficiency apparently aggravated pressure overload-induced cardiac hypertrophy and fibrosis as well as impaired cardiac function, whereas cardiac-specific overexpression of DUPS12 was capable of reversing this hypertrophic and fibrotic phenotype and improving contractile function. Furthermore, we demonstrated that JNK1/2 activity but neither ERK1/2 nor p38 activity was increased in the DUSP12 deficient group and decreased in the DUSP12 overexpression group both in vitro and in vivo under hypertrophic stress conditions. Pharmacological inhibition of JNK1/2 activity (SP600125) is capable of reversing the hypertrophic phenotype in DUSP12 knockout (KO) mice. DUSP12 protects against pathological cardiac hypertrophy and related pathologies. This regulatory role of DUSP12 is primarily through c-Jun N-terminal kinase (JNK) inhibition. DUSP12 could be a promising therapeutic target of pathological cardiac hypertrophy. DUSP12 is down-regulated in hypertrophic hearts. An absence of DUSP12 aggravated cardiac hypertrophy, whereas cardiomyocyte-specific DUSP12 overexpression can alleviate this hypertrophic phenotype with improved cardiac function. Further study demonstrated that DUSP12 inhibited JNK activity to attenuate pathological cardiac hypertrophy.

scholarly journals Cardiac Overexpression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice

2004 ◽  
Vol 279 (19) ◽  
pp. 20422-20434 ◽  
Author(s):  
Sagartirtha Sarkar ◽  
Douglas W. Leaman ◽  
Sudhiranjan Gupta ◽  
Parames Sil ◽  
David Young ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Gene Clusters ◽  
The United States ◽  
Cellular Interaction ◽  
Marker Genes ◽  
Human Heart Failure

Cardiac hypertrophy and heart failure remain leading causes of death in the United States. Many studies have suggested that, under stress, myocardium releases factors triggering protein synthesis and stimulating myocyte growth. We identified and cloned myotrophin, a 12-kDa protein from hypertrophied human and rat hearts. Myotrophin (whose gene is localized on human chromosome 7q33) stimulates myocyte growth and participates in cellular interaction that initiates cardiac hypertrophyin vitro. In this report, we present data on the pathophysiological significance of myotrophinin vivo, showing the effects of overexpression of cardio-specific myotrophin in transgenic mice in which cardiac hypertrophy occurred by 4 weeks of age and progressed to heart failure by 9-12 months. This hypertrophy was associated with increased expression of proto-oncogenes, hypertrophy marker genes, growth factors, and cytokines, with symptoms that mimicked those of human cardiomyopathy, functionally and morphologically. This model provided a unique opportunity to analyze gene clusters that are differentially up-regulated during initiation of hypertrophyversustransition of hypertrophy to heart failure. Importantly, changes in gene expression observed during initiation of hypertrophy were significantly different from those seen during its transition to heart failure. Our data show that overexpression of myotrophin results in initiation of cardiac hypertrophy that progresses to heart failure, similar to changes in human heart failure. Knowledge of the changes that take place as a result of overexpression of myotrophin at both the cellular and molecular levels will suggest novel strategies for treatment to prevent hypertrophy and its progression to heart failure.

scholarly journals The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure

2019 ◽  
Vol 316 (1) ◽  
pp. H186-H200 ◽  
Author(s):  
Ju Youn Beak ◽  
Hong Soon Kang ◽  
Wei Huang ◽  
Page H. Myers ◽  
Dawn E. Bowles ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Myocardial Hypertrophy ◽  
Orphan Receptor ◽  
Ang Ii ◽  
Pathological Hypertrophy

The nuclear receptor retinoic acid-related orphan receptor-α (RORα) regulates numerous critical biological processes, including central nervous system development, lymphocyte differentiation, and lipid metabolism. RORα has been recently identified in the heart, but very little is known about its role in cardiac physiology. We sought to determine whether RORα regulates myocardial hypertrophy and cardiomyocyte survival in the context of angiotensin II (ANG II) stimulation. For in vivo characterization of the function of RORα in the context of pathological cardiac hypertrophy and heart failure, we used the “staggerer” (RORαsg/sg) mouse, which harbors a germline mutation encoding a truncated and globally nonfunctional RORα. RORαsg/sg and wild-type littermate mice were infused with ANG II or vehicle for 14 days. For in vitro experiments, we overexpressed or silenced RORα in neonatal rat ventricular myocytes (NRVMs) and human cardiac fibroblasts exposed to ANG II. RORαsg/sg mice developed exaggerated myocardial hypertrophy and contractile dysfunction after ANG II treatment. In vitro gain- and loss-of-function experiments were consistent with the discovery that RORα inhibits ANG II-induced pathological hypertrophy and cardiomyocyte death in vivo. RORα directly repressed IL-6 transcription. Loss of RORα function led to enhanced IL-6 expression, proinflammatory STAT3 activation (phopho-STAT3 Tyr705), and decreased mitochondrial number and function, oxidative stress, hypertrophy, and death of cardiomyocytes upon ANG II exposure. RORα was less abundant in failing compared with nonfailing human heart tissue. In conclusion, RORα protects against ANG II-mediated pathological hypertrophy and heart failure by suppressing the IL-6-STAT3 pathway and enhancing mitochondrial function. NEW & NOTEWORTHY Mice lacking retinoic acid-related orphan receptor-α (RORα) develop exaggerated cardiac hypertrophy after angiotensin II infusion. Loss of RORα leads to enhanced IL-6 expression and NF-κB nuclear translocation. RORα maintains mitochondrial function and reduces oxidative stress after angiotensin II. The abundance of RORα is reduced in failing mouse and human hearts.

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