scholarly journals Cardiac-Specific PID1 Overexpression Enhances Pressure Overload-Induced Cardiac Hypertrophy in Mice

2015 ◽  
Vol 35 (5) ◽  
pp. 1975-1985 ◽  
Author(s):  
Yaoqiu Liu ◽  
Yahui Shen ◽  
Jingai Zhu ◽  
Ming Liu ◽  
Xing Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Mapk Pathway ◽  
Pressure Overload ◽  
Wild Type Mouse ◽  
Heart Tissue ◽  
Wild Type ◽  
Heart Transplants ◽  
Over Expression

Background/Aims: PID1 was originally described as an insulin sensitivity relevance protein, which is also highly expressed in heart tissue. However, its function in the heart is still to be elucidated. Thus this study aimed to investigate the role of PID1 in the heart in response to hypertrophic stimuli. Methods: Samples of human failing hearts from the left ventricles of dilated cardiomyopathy (DCM) patients undergoing heart transplants were collected. Transgenic mice with cardiomyocyte-specific overexpression of PID1 were generated, and cardiac hypertrophy was induced by transverse aortic constriction (TAC). The extent of cardiac hypertrophy was evaluated by echocardiography as well as pathological and molecular analyses of heart samples. Results: A significant increase in PID1 expression was observed in failing human hearts and TAC-treated wild-type mouse hearts. When compared with TAC-treated wild-type mouse hearts, PID1-TG mouse showed a significant exacerbation of cardiac hypertrophy, fibrosis, and dysfunction. Further analysis of the signaling pathway in vivo suggested that these adverse effects of PID1 were associated with the inhibition of AKT, and activation of MAPK pathway. Conclusion: Under pathological conditions, over-expression of PID1 promotes cardiac hypertrophy by regulating the Akt and MAPK pathway.

Abstract 837: Beta1 And Beta2 Adrenergic Receptor Transgenic Mice Display Distinct MicroRNA Expression Patterns That Converge On The Hypertrophic Signature

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Danish Sayed ◽  
Shweta Rane ◽  
Leng-Yi Chen ◽  
Minzhen He ◽  
Jacqueline Lypowy ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Adrenergic Receptor ◽  
Mapk Pathway ◽  
Expression Patterns ◽  
Pressure Overload ◽  
Mapk Signaling ◽  
Compensatory Hypertrophy ◽  
Over Expression ◽  
Mrna Targets ◽  
Dose Dependent

MicroRNA (miRNA) are ~22 ribonucleotides-long, with a potential to recognize multiple mRNA targets guided by sequence complimentarity. This class of molecules is functionally versatile, with the capacity to specifically inhibit translation, as well as, induce mRNA degradation, through targeting the 3′-untranslated regions. The levels of individual miRNA vary under different developmental, biological, or pathological conditions, thus, implicating them in normal and pathological cellular attributes. We have previously reported a miRNA signature that distinguishes pressure-overload compensatory hypertrophy by recapitulating the neonatal pattern. We hypothesized that this ’signature’ might aid in discriminating the underlying molecular differences in genetic models of cardiac hypertrophy, as seen in the beta1 and 2 adrenergic receptor (B1AR and B2AR) transgenic (Tg) mice. To address this, we used microarray analysis of RNA isolated from the hearts of 3 months old B1AR and B2AR mice. In general, while both mice exhibited an overlap with the hypertrophy signature including, upregulation of miR-21 and downregulation of miR-133a, miR-133b, and miR-185, the B2-AR Tg exhibited a more extensive overlap with the hypertrophy pattern, which further included upregulation of miR-199a*, miR-214, and miR-15b. To understand the functional significance of these miRNA in myocyte hypertrophy, we cloned them and their anti-sense sequences into adenoviral vectors. Significantly, over-expression miR-21 resulted in a, dose-dependent, branching (sprouting) of the cells. Computational predictions by ’TargetScanS’ identified sprouty as potential target. Subsequently, we confirmed down-regulation of sprouty by over-expression of miR-21 and vice versa. Sprouty is a known inhibitor of the Ras-MAPK signaling pathway and is, concordantly, downregulated in many forms of cancer. In the heart, sprouty has been suggested to control myocyte size and vascularization during cardiac hypertrophy. Thus, we propose that B1AR and B2AR Tg models exhibit distinct miRNA profiles that converge on that of pressure-overload cardiac hypertrophy. Moreover, the commonly over-expressed miR-21 plays a role in downregulating sprouty, an antagonist of the Ras-MAPK pathway.

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.

scholarly journals Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca 2+ Handling After Pressure Overload

Circulation ◽  
2020 ◽  
Vol 141 (3) ◽  
pp. 199-216 ◽  
Author(s):  
Fiona Bartoli ◽  
Marc A. Bailey ◽  
Baptiste Rode ◽  
Philippe Mateo ◽  
Fabrice Antigny ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Specific Expression ◽  
Channel Inhibition

Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca 2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. Methods: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery. Results: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn 2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca 2+ signaling alterations (increased SOCE, decreased [Ca 2+ ] i transients amplitude and decay rate, lower SR Ca 2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult. Conclusions: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.

Abstract 59: Role of Follistatin 315 in Regulating Cardiac Hypertrophy in Physiology and Pathophysiology

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Zhaobin Xu ◽  
Alisa D Blazek ◽  
Eric Beck ◽  
Jenna Alloush ◽  
Jackie Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Surface ◽  
Cardiac Hypertrophy ◽  
Genetically Modified ◽  
Pressure Overload ◽  
Wild Type ◽  
Surface Binding ◽  
Post Surgery ◽  
Genetically Modified Mice

Heart failure is characterized by initial compensatory changes, including the myocyte hypertrophy, chamber dilation, and matrix remodeling, that proceed until progressive dysfunction produces end stage heart failure and mortality. Recently, the roles of secreted factors in the heart that could regulate pathological hypertrophy, including follistatin (FST) and related molecules, have been examined by various investigators. FST is a molecule that blocks secretion of follicle-stimulating hormone from the pituitary and regulates members of the transforming growth factor beta (TGF-β) family including myostatin. Here we tested the effects of a particular FST isoform, FST288, on heart function in mice. The gene encoding FST produces three isoforms that differ in biological activities and cell surface binding capabilities. The FST315 isoform contains all six exons, and proteolytic cleavage of the FST315 C-terminal tail results in production of FST303. The lack of exon 6, which codes for the acidic C-terminal tail of the putative full-length protein, results in FST288. The missing acidic C-terminal tail region found in soluble FST315 allows FST288 to bind cell surface heparin-sulfated proteoglycans, accounting for the differential actions of these FST isoforms. Since mice that are null for the FST gene die embryonically, we used genetically modified mice that express only the FST288 isoform to test the role of FST315 in adult heart. Examination of these animals suggests that the loss of FST315 expression has limited effects on the heart at the resting state. When these mice are subjected to pressure overload through transverse aortic constriction (TAC) surgery they appear to be resistant to the compensatory cardiac hypertrophy present in wild type mice by 4 weeks post surgery. Both cardiac structure (examined by histology) and function (as measured by echocardiography and pressure/volume loops) following TAC are improved in the genetically modified mice when compared to wild type mice. This response is likely due to modification of the myostatin signaling pathway, one of the major targets of FST315. Overall, our data illustrates that FST315 is an important contributor to the progression of pressure overload induced cardiac hypertrophy.

scholarly journals Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy

2001 ◽  
Vol 38 (3) ◽  
pp. 876-882 ◽  
Author(s):  
Antonio Rapacciuolo ◽  
Giovanni Esposito ◽  
Kathleen Caron ◽  
Lan Mao ◽  
Steven A Thomas ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload

scholarly journals Allosteric Regulation of Na/Ca Exchange Current by Cytosolic Ca in Intact Cardiac Myocytes

2001 ◽  
Vol 117 (2) ◽  
pp. 119-132 ◽  
Author(s):  
Christopher R. Weber ◽  
Kenneth S. Ginsburg ◽  
Kenneth D. Philipson ◽  
Thomas R. Shannon ◽  
Donald M. Bers
Keyword(s):  
Cardiac Myocytes ◽  
Allosteric Regulation ◽  
Wild Type Mouse ◽  
Wild Type ◽  
Physiological Conditions ◽  
Model Predictions ◽  
Electrochemical Effect ◽  
Fine Tune

The cardiac sarcolemmal Na-Ca exchanger (NCX) is allosterically regulated by [Ca]i such that when [Ca]i is low, NCX current (INCX) deactivates. In this study, we used membrane potential (Em) and INCX to control Ca entry into and Ca efflux from intact cardiac myocytes to investigate whether this allosteric regulation (Ca activation) occurs with [Ca]i in the physiological range. In the absence of Ca activation, the electrochemical effect of increasing [Ca]i would be to increase inward INCX (Ca efflux) and to decrease outward INCX. On the other hand, Ca activation would increase INCX in both directions. Thus, we attributed [Ca]i-dependent increases in outward INCX to allosteric regulation. Ca activation of INCX was observed in ferret myocytes but not in wild-type mouse myocytes, suggesting that Ca regulation of NCX may be species dependent. We also studied transgenic mouse myocytes overexpressing either normal canine NCX or this same canine NCX lacking Ca regulation (Δ680–685). Animals with the normal canine NCX transgene showed Ca activation, whereas animals with the mutant transgene did not, confirming the role of this region in the process. In native ferret cells and in mice with expressed canine NCX, allosteric regulation by Ca occurs under physiological conditions (KmCaAct = 125 ± 16 nM SEM ≈ resting [Ca]i). This, along with the observation that no delay was observed between measured [Ca]i and activation of INCX under our conditions, suggests that beat to beat changes in NCX function can occur in vivo. These changes in the INCX activation state may influence SR Ca load and resting [Ca]i, helping to fine tune Ca influx and efflux from cells under both normal and pathophysiological conditions. Our failure to observe Ca activation in mouse myocytes may be due to either the extent of Ca regulation or to a difference in KmCaAct from other species. Model predictions for Ca activation, on which our estimates of KmCaAct are based, confirm that Ca activation strongly influences outward INCX, explaining why it increases rather than declines with increasing [Ca]i.

The MAPK ERK1 Is a Sensor of the Steady-State Splenic Erythropoiesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 73-73
Author(s):  
Soizic Guihard ◽  
Denis Clay ◽  
Laurence Cocault ◽  
Paule Opolon ◽  
Michele Souyri ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Surface ◽  
Mapk Pathway ◽  
Surface Expression ◽  
Specific Role ◽  
Cell Surface Expression ◽  
Wild Type ◽  
Erk Mapk

Abstract Abstract 73 In different culture models, conflicting results have been obtained with respect to the role of the ERK/MAPK pathway and the ERK kinases on erythropoiesis. There is no in vivo experimental data on the role of these kinases in adult erythropoeisis. The existence of two ERK isoforms (ERK1 and ERK2) suggests that they could play specific role, based on their expression, their activation level and/or the ratio between both of them. The ERK1−/− mice were used to study this hypothesis. Increased number of circulating erythrocytes, increased hemoglobin level and hematocrit were found in these mice. The deletion of ERK1 leads to an uncontrolled splenic erythropoiesis while the bone marrow erythropoiesis remains normal. The ERK1−/− mice display splenomegaly characterized by a marked expansion of the red pulp and an increased number in basophilic (Ery.A) and late basophilic (Ery.B) erythroblasts. This impaired erythropoiesis in ERK1−/− mice is cell autonomous as shown by bone marrow transplantation experiments. This splenic erythropoiesis is not due to an overexpression or overactivation of the ERK2 isoform in erythroblasts. It has been shown that Fas-mediated apoptosis of erythroblasts would limit the basal erythropoietic rate. In ERK1−/− mice, Ery.A expansion is associated with a decrease in cell surface expression of both Fas and FasL as compared with wild-type mice. This fall in Fas/FasL expression is correlated with a decrease in Annexin V binding on splenic Ery.A and Ery.B. In addition, cell cycle analysis revealed an increased S-phase in ERK1−/− Ery.A cells compared with wild-type Ery.A. In conclusion, these data demonstrate for the first time the in vivo involvement of the ERK/MAPK pathway in adult splenic erythropoiesis and underlies the specific role of ERK1 in this function. By regulating the cell surface expression of Fas and FasL on splenic erythroblasts, ERK1 acts as a sensor of the basal erythropoietic rate. Disclosures: No relevant conflicts of interest to declare.

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 How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na+ pumps are crucial

2017 ◽  
Vol 313 (5) ◽  
pp. H919-H930 ◽  
Author(s):  
Mordecai P. Blaustein
Keyword(s):  
Cardiac Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Genetically Engineered ◽  
Wild Type ◽  
Ouabain Binding ◽  
Transaortic Constriction ◽  
Endogenous Ouabain

Left ventricular hypertrophy is frequently observed in hypertensive patients and is believed to be due to the pressure overload and cardiomyocyte stretch. Three recent reports on mice with genetically engineered Na+ pumps, however, have demonstrated that cardiac ouabain-sensitive α2-Na+ pumps play a key role in the pathogenesis of transaortic constriction-induced hypertrophy. Hypertrophy was delayed/attenuated in mice with mutant, ouabain-resistant α2-Na+ pumps and in mice with cardiac-selective knockout or transgenic overexpression of α2-Na+ pumps. The latter, seemingly paradoxical, findings can be explained by comparing the numbers of available (ouabain-free) high-affinity (α2) ouabain-binding sites in wild-type, knockout, and transgenic hearts. Conversely, hypertrophy was accelerated in α2-ouabain-resistant (R) mice in which the normally ouabain-resistant α1-Na+ pumps were mutated to an ouabain-sensitive (S) form (α1S/Sα2R/R or “SWAP” vs. wild-type or α1R/R α2S/S mice). Furthermore, transaortic constriction-induced hypertrophy in SWAP mice was prevented/reversed by immunoneutralizing circulating endogenous ouabain (EO). These findings show that EO and its receptor, ouabain-sensitive α2, are critical factors in pressure overload-induced cardiac hypertrophy. This complements reports linking elevated plasma EO to hypertension, cardiac hypertrophy, and failure in humans and elucidates the underappreciated role of the EO-Na+ pump pathway in cardiovascular disease.

scholarly journals Targeting E3 Ubiquitin-Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination

Circulation ◽  
2021 ◽  
Author(s):  
Dingsheng Zhao ◽  
Guohui Zhong ◽  
Jianwei Li ◽  
Junjie Pan ◽  
Yinlong Zhao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Heart Function ◽  
Pressure Overload ◽  
Direct Interaction ◽  
Adequate Treatment ◽  
Virus Serotype ◽  
Gene Assay

Background: Without adequate treatment, pathological cardiac hypertrophy induced by sustained pressure overload eventually leads to HF (HF). WW domain- containing E3 ubiquitin protein ligase 1 (WWP1) is an important regulator of aging-related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload-induced cardiac remodeling and HF is yet to be determined. Methods: To examine the correlation of WWP1 with hypertrophy, we analyzed WWP1 expression in patients with HF and mice subjected to transverse aortic constriction (TAC) by Western blotting and immunohistochemical staining. TAC surgery was performed on WWP1 knockout (KO) mice to assess the role of WWP1 in cardiac hypertrophy, heart function was examined by echocardiography and related cellular and molecular markers were examined. Mass spectrometry and coimmunoprecipitation assays were conducted to identify the proteins that interacted with WWP1. Pulse-chase assay, ubiquitination assay, reporter gene assay and an in vivo mouse model via adeno-associated virus serotype 9 (AAV9) were used to explore the mechanisms by which WWP1 regulates cardiac remodeling. AAV9 carrying cTnT promoter driven small hairpin RNA targeting WWP1 (AAV9-cTnT-shWWP1) was administered to investigate its rescue role in TAC-induced cardiac dysfunction. Results: The WWP1 level was significantly increased in the hypertrophic hearts from patients with HF and mice subjected to TAC. The results of echocardiography and histology demonstrated that WWP1 KO protected the heart from TAC-induced hypertrophy. There was a direct interaction between WWP1 and disheveled segment polarity protein 2 (DVL2). DVL2 was stabilized by WWP1 mediated K27-linked polyubiquitination. The role of WWP1 in pressure overload-induced cardiac hypertrophy was mediated by the DVL2/CaMKII/HDAC4/MEF2C signaling pathway. Therapeutic targeting WWP1 almost abolished TAC induced heart dysfunction, suggesting WWP1 as a potential target for treating cardiac hypertrophy and failure. Conclusions: We identified WWP1 as a key therapeutic target for pressure overload induced cardiac remodeling. We also found a novel mechanism regulated by WWP1. WWP1 promotes atypical K27-linked ubiquitin multichain assembly on DVL2 and exacerbates cardiac hypertrophy by the DVL2/CaMKII/HDAC4/MEF2C pathway.

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