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.

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.

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.

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

Hypertension ◽  
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.

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.

scholarly journals Nobiletin, a Polymethoxy Flavonoid, Protects Against Cardiac Hypertrophy Induced by Pressure-Overload via Inhibition of NAPDH Oxidases and Endoplasmic Reticulum Stress

2017 ◽  
Vol 42 (4) ◽  
pp. 1313-1325 ◽  
Author(s):  
Ning Zhang ◽  
Wen-Ying Wei ◽  
Zheng Yang ◽  
Yan Che ◽  
Ya-Ge Jin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cardiac Hypertrophy ◽  
Er Stress ◽  
Disease Onset ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Aortic Banding

Background/Aims: An increase in oxidative stress has been implicated in the pathophysiology of pressure-overload induced cardiac hypertrophy. Nobiletin (NOB), extracted from the fruit peel of citrus, possesses anti-oxidative property. Our study aimed to investigate the protective role of NOB in the progression of cardiac hypertrophy in vivo and in vitro. Methods: Mice received aortic banding (AB) operation to induce cardiac hypertrophy. Experimental groups were as follows: sham+vehicle (VEH/SH), sham+NOB (NOB/SH), AB+vehicle (VEH/AB), and AB+ NOB (NOB/AB). Animals (n = 15 per group) were treated with vehicle or NOB (50 mg/kg) for 4 weeks after disease onset. Results: NOB prevented cardiac hypertrophy induced by aortic banding (AB), as assessed by the cross-sectional area of cardiomyocytes, heart weight-to-body weight ratio, gene expression of hypertrophic markers and cardiac function. In addition, NOB supplementation blunted the increased expression of NAPDH oxidase (NOX) 2 and NOX4 and mitigated endoplasmic reticulum (ER) stress and myocyte apoptosis in cardiac hypertrophy. Furthermore, NOB treatment attenuated the neonatal rat cardiomyocyte (NRCM) hypertrophic response stimulated by phenylephrine (PE) and alleviated ER stress. However, our data showed that NOB dramatically inhibited NOX2 expression but not NOX4 in vitro. Finally, we found that knockdown of NOX2 attenuated ER stress in NRCMs stimulated by PE. Conclusions: Inhibition of oxidative and ER stress by NOB in the myocardium may represent a potential therapy for cardiac hypertrophy. Moreover, there is a direct role of NOX2 in regulating ER stress stimulated by PE.

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.

Abstract P317: Cardiac Fibroblast GSK3α Promotes Myocardial Fibrotic Remodeling Through GSK3α-ERK-IL11 Signaling Circuit

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Prachi Umbarkar ◽  
Sultan Tousif ◽  
Anand P Singh ◽  
Joshua C Anderson ◽  
qinkun zhang ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Collagen Gel ◽  
Pressure Overload ◽  
Negative Regulator ◽  
Post Injury

Background: Myocardial fibrosis contributes significantly to heart failure (HF). Fibroblasts are among the predominant cell type in the heart and are primary drivers of fibrosis. To identify the kinases involved in fibrosis, we analyzed the kinome of mouse cardiac fibroblasts (CF) isolated from normal and failing hearts. This unbiased screening revealed the critical role of the GSK-3 family-centric pathways in fibrosis. Previously we have shown that among two isoforms of GSK3, CF-GSK3β acts as a negative regulator of fibrosis in the injured heart. However, the role of CF-GSK3α in the pathogenesis of cardiac diseases is completely unknown. Methods and Results: To define the role of CF-GSK3α in HF, we employed two novel fibroblast-specific KO mouse models. Specifically, GSK3α was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or periostin- promoter-driven Cre recombinase. In both models, GSK3α deletion restricted pressure overload-induced cardiac fibrosis and preserved cardiac function. We examined the effect of GSK3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signaling in vitro . A significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1-treated KO CFs confirmed that GSK3α is required for myofibroblast transformation. Surprisingly, GSK3α deletion did not affect SMAD3 activation, indicating the pro-fibrotic role of GSK3α is SMAD3 independent. To further delineate the underlying mechanisms, proteins were isolated from CFs of WT and KO mice at 4 weeks post-injury, and kinome profiling was performed. The kinome analysis identified the downregulation of RAF family kinase activity in KO CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. Consistently, flow cytometric analysis of CFs confirmed significantly low levels of pERK in KO mice. Additionally, our in vitro studies demonstrated that GSK3α deletion prevents TGFβ1-induced ERK activation. Interestingly, IL-11, a pro-fibrotic downstream effector of TGFβ1, was remarkably reduced in KO CFs and ERK inhibition further decreased IL-11 expression. Taken together, herein, we discovered the GSK3α-ERK-IL-11 signaling as a critical pro-fibrotic pathway in the heart. Strategies to inhibit this pro-fibrotic network could prevent adverse fibrosis and HF. Conclusion: CF-GSK3α plays a causal role in myocardial fibrosis that could be therapeutically targeted for future clinical applications.

scholarly journals Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling

Hypertension ◽  
2021 ◽  
Author(s):  
Yuhao Zhang ◽  
Sheng-an Su ◽  
Wudi Li ◽  
Yuankun Ma ◽  
Jian Shen ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ion Channel ◽  
Calcium Homeostasis ◽  
Pressure Overload ◽  
Cell Physiology ◽  
Hypertrophic Growth ◽  
Molecular Features ◽  
Mechanosensitive Ion Channel

Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca 2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1 fl/fl Myh6Cre+, Piezo1 Cko ) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca 2+ influx and intracellular Ca 2+ overload, thereby increased the activation of Ca 2+ -dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.

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

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.

Abstract P189: RhoA Functions as an Antihypertrophic Switch in the Mouse Heart

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Davy Vanhoutte ◽  
Jop Van Berlo ◽  
Allen J York ◽  
Yi Zheng ◽  
Jeffery D Molkentin
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Small Gtpase ◽  
Mouse Heart ◽  
Activity Levels ◽  
Lung Weight ◽  
Pathological Cardiac Hypertrophy ◽  
Rhoa Protein

Background. Small GTPase RhoA has been previously implicated as an important signaling effector within the cardiomyocyte. However, recent studies have challenged the hypothesized role of RhoA as an effector of cardiac hypertrophy. Therefore, this study examined the in vivo role of RhoA in the development of pathological cardiac hypertrophy. Methods and results . Endogenous RhoA protein expression and activity levels (GTP-bound) in wild-type hearts were significantly increased after pressure overload induced by transverse aortic constriction (TAC). To investigate the necessity of RhoA within the adult heart, RhoA-LoxP-targeted (RhoA flx/flx ) mice were crossed with transgenic mice expressing Cre recombinase under the control of the endogenous cardiomyocyte-specific β-myosin heavy chain (β-MHC) promoter to generate RhoA βMHC-cre mice. Deletion of RhoA with β-MHC-Cre produced viable adults with > 85% loss of RhoA protein in the heart, without altering the basic architecture and function of the heart compared to control hearts, at both 2 and 8 months of age. However, subjecting RhoA βMHC-cre hearts to 2 weeks of TAC resulted in marked increase in cardiac hypertrophy (HW/BW (mg/g): 9.5 ± 0.3 for RhoA βMHC-cre versus 7.7 ± 0.4 for RhoA flx/flx ; and cardiomyocyte size (mm 2 ): 407 ± 21 for RhoA βMHC-cre versus 262 ± 8 for RhoA flx/flx ; n ≥ 8 per group; p<0.01) and a significantly increased fibrotic response. Moreover, RhoA βMHC-cre hearts transitioned more quickly into heart failure whereas control mice maintained proper cardiac function (fractional shortening (%): 23.3 ± 1.2 for RhoA βMHC-cre versus 29.3 ± 1.2 for RhoA flx/flx ; n ≥ 8 per group; p<0.01; 12 weeks after TAC). The latter was further associated with a significant increase in lung weight normalized to body weight and re-expression of the cardiac fetal gene program. In addition, these mice also displayed greater cardiac hypertrophy in response to 2 weeks of angiotensinII/phenylephrine infusion. Conclusion. These data identify RhoA as an antihypertrophic molecular switch in the mouse heart.

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