A novel phospho-acceptor site controls nuclear import of histone deacetylase 9, a negative regulator of 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.

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Abstract 197: Overexpression of the Na+/K+ ATPase a2 But Not a1 Isoform Attenuates Pathological Cardiac Hypertrophy and Remodeling

Circulation Research ◽

10.1161/res.113.suppl_1.a197 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Robert N Correll ◽

Petra Eder ◽

Adam R Burr ◽

Sanda Despa ◽

Jennifer Davis ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Protective Effect ◽

Pressure Overload ◽

Negative Regulator ◽

Protective Measure ◽

Nuclear Factor ◽

Activated T Cells ◽

Reverse Mode ◽

Pathological Cardiac Hypertrophy ◽

Protein Kinase Cα

The Na+/K+ ATPase (NKA) directly regulates intracellular Na+ levels, which indirectly regulate Ca2+ levels by controlling flux through the Na+/Ca2+ exchanger (NCX1). Elevated Na+ levels have been reported during heart failure, which permits some degree of reverse mode Ca2+ entry through NCX1 and less efficient Ca2+ clearance. To determine if lower intracellular Na+ levels would enhance forward-mode Ca2+ clearance and prevent reverse-mode Ca2+ entry through NCX1 as a protective measure, we generated cardiac-specific transgenic mice overexpressing either the NKA-α1 or α2 isoform and subjected them to pressure overload hypertrophic stimulation. We found that while increased expression of the NKA-α1 isoform had no protective effect, overexpression of NKA-α2 significantly decreased cardiac hypertrophy after pressure overload at 2, 10 and 16 weeks of stimulation. Remarkably, total NKA protein expression was not altered in either of these 2 transgenic models, as increased expression of one isoform led to a concomitant decrease in the other endogenous isoform. While total NKA ATPase activity and intracellular Na+ levels were unchanged in either overexpression model, and both showed reduced Ca2+ transient amplitudes and sarcoplasmic reticulum Ca2+ load, only NKA-α2 overexpression led to faster removal of bulk Ca2+ from the cytosol in a manner requiring NCX1 activity. This increased NCX1 activity, though correlated with improved outcome after pressure overload, did not affect signaling through Ca2+-sensitive signaling pathways such as calcineurin/nuclear factor of activated T-cells, Ca2+/calmodulin-dependent kinase II, or protein kinase Cα. Overexpression of NKA-α2 did, however, result in reduced expression of phospholemman (PLM), an inhibitor of NKA activity (when dephosphorylated) and NCX1 activity (when phosphorylated). Our results suggest that the protective effect produced by increased expression of NKA-α2 after pressure overload is likely due to: 1) Na+ regulation in a unique signaling microdomain distinct from NKA-α1, and 2) downregulation of PLM expression that removes a negative regulator of NCX1 activity, both leading to preservation of forward-mode NCX1 activity during disease, in association with optimized cardiac function.

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Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Hypertension ◽

10.1161/hypertensionaha.116.07392 ◽

2016 ◽

Vol 67 (6) ◽

pp. 1237-1248 ◽

Cited By ~ 20

Author(s):

Ben He ◽

Yi-Chao Zhao ◽

Ling-Chen Gao ◽

Xiao-Ying Ying ◽

Long-Wei Xu ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Negative Regulator ◽

Pathological Cardiac Hypertrophy ◽

Specific Protease ◽

Ubiquitin Specific Protease

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

Hypertension ◽

10.1161/hyp.68.suppl_1.p235 ◽

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.

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Abstract 298: Irisin is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Circulation Research ◽

10.1161/res.123.suppl_1.298 ◽

2018 ◽

Vol 123 (Suppl_1) ◽

Author(s):

Yifan Zhao ◽

Yawei Xu ◽

Wenhui Peng

Keyword(s):

Cardiac Hypertrophy ◽

Negative Regulator ◽

Pathological Cardiac Hypertrophy

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Histone Deacetylase 9 Is a Negative Regulator of Adipogenic Differentiation

Journal of Biological Chemistry ◽

10.1074/jbc.m111.262964 ◽

2011 ◽

Vol 286 (31) ◽

pp. 27836-27847 ◽

Cited By ~ 85

Author(s):

Tapan K. Chatterjee ◽

Gila Idelman ◽

Victor Blanco ◽

Andra L. Blomkalns ◽

Mark G. Piegore ◽

...

Keyword(s):

Histone Deacetylase ◽

Adipogenic Differentiation ◽

Negative Regulator ◽

Histone Deacetylase 9

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STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) Inhibits Pathological Cardiac Hypertrophy

Hypertension ◽

10.1161/hypertensionaha.120.14752 ◽

2020 ◽

Vol 76 (4) ◽

pp. 1219-1230

Author(s):

Peng-Long Li ◽

Hui Liu ◽

Guo-Peng Chen ◽

Ling Li ◽

Hong-Jie Shi ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Molecular Mechanisms ◽

Pressure Overload ◽

Small Gtpase ◽

Negative Regulator ◽

Mitogen Activated Protein Kinase ◽

Neonatal Rat ◽

Signaling Cascade ◽

Rat Cardiomyocytes ◽

Pathological Cardiac Hypertrophy

Pathological cardiac hypertrophy is one of the major predictors and inducers of heart failure, the end stage of various cardiovascular diseases. However, the molecular mechanisms underlying pathogenesis of pathological cardiac hypertrophy remain largely unknown. Here, we provided the first evidence that STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) is a key negative regulator of this disease. We found that the expression of STEAP3 was reduced in pressure overload-induced hypertrophic hearts and phenylephrine-induced hypertrophic cardiomyocytes. In a transverse aortic constriction-triggered mouse cardiac hypertrophy model, STEAP3 deficiency remarkably deteriorated cardiac hypertrophy and fibrosis, whereas the opposite phenotype was observed in the cardiomyocyte-specific STEAP3 overexpressing mice. Accordingly, STEAP3 significantly mitigated phenylephrine-induced cell enlargement in primary neonatal rat cardiomyocytes. Mechanistically, via RNA-seq and immunoprecipitation-mass screening, we demonstrated that STEAP3 directly bond to Rho family small GTPase 1 and suppressed the activation of downstream mitogen-activated protein kinase-extracellular signal-regulated kinase signaling cascade. Remarkably, the antihypertrophic effect of STEAP3 was largely blocked by overexpression of constitutively active mutant Rac1 (G12V). Our study indicates that STEAP3 serves as a novel negative regulator of pathological cardiac hypertrophy by blocking the activation of the Rac1-dependent signaling cascade and may contribute to exploring effective therapeutic strategies of pathological cardiac hypertrophy treatment.

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Abstract P234: CTMP Negatively Regulates Pathological Cardiac Hypertrophy via Akt-dependent Manner

Hypertension ◽

10.1161/hyp.68.suppl_1.p234 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Hongliang Li ◽

Ke-Qiong Deng ◽

Xiao-Jing Zhang

Keyword(s):

Cardiac Hypertrophy ◽

Knockout Mice ◽

Pressure Overload ◽

Akt Signaling ◽

Negative Regulator ◽

Dependent Manner ◽

Loss Of Function ◽

Akt Inhibitor ◽

Pathological Cardiac Hypertrophy

Pathological cardiac hypertrophy which represents a leading cause of morbidity and mortality worldwide is a pathological process related to multifactorial and multiple molecules and regulated by numerous signaling pathways. Deregulation of AKT signaling is important in cardiac hypertrophy and cardiac dysfunction, but the underlying mechanism is not fully understood. In this study, we identified carboxy-terminal modulator protein (CTMP), an endogenous AKT inhibitor, as a key regulator of cardiac hypertrophy in response to pressure overload. Our results demonstrated that CTMP levels were downregulated by about 40% in aortic banding (AB)–induced hypertrophied mice hearts and 50% in failing human hearts compared to their controls respectively. Mice overexpressing CTMP specifically in the heart were resistant to AB-induced cardiac hypertrophy, whereas cardiac-specific conditional CTMP-knockout mice exhibited an aggravated phenotype induced by pressure overload. Additionally, gain-or-loss of function experiments mediated by adenovirus demonstrated that CTMP also prevented an angiotensin II–induced hypertrophic response in isolated cardiomyocytes in vitro . Mechanistically, we discovered that AKT signaling was significantly activated in AB-treated WT hearts, which was blocked by cardiac overexpression of CTMP, whereas being enhanced by loss of CTMP in response to chronic pressure overload and agonist stimulation. Moreover, rescue-experiments revealed that inhibition of AKT activation through LY294002 ameliorated the cardiac abnormalities in CTMP-knockout mice after AB. Taken together, our present study provides both in vitro and in vivo evidences that CTMP functions as a novel negative regulator factor of pathological cardiac hypertrophy. The underlying mechanisms responsible for CTMP-elicited effects are dependent on the inhibition of AKT signaling. The above-mentioned findings also expand our knowledge of the mechanisms of cardiac hypertrophy and provide potential therapeutic targets for pathological cardiac hypertrophy and heart failure.

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