Inhibition of p38α MAPK rescues cardiomyopathy induced by overexpressed β2-adrenergic receptor, but not β1-adrenergic receptor

Peter, P; Brady, Jennifer E.; Yan, Lin; Chen, Wei; Engelhardt, Stefan; Wang, Yibin; Sadoshima, Junichi; Vatner, Stephen F.; Vatner, Dorothy E.

doi:10.1172/jci29576

Cited by 55 publications

(59 citation statements)

References 42 publications

(69 reference statements)

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“…Another interesting possibility raised by our findings is that modulation of MAPK and other signaling pathways might mediate some of the phenotypic effects of perturbation of class IIa HDACs in different tissues such as endothelium, bone, and myocardium. This idea is supported the finding that p38 has been implicated in the development of hypertrophic cardiomyopathy in mouse models (48).…”

Section: Discussionsupporting

confidence: 69%

Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes

Kasler

Young

Mottet

et al. 2011

The Journal of Immunology

101

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CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC)7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in mouse thymocytes and that it regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR Jα segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAPK activity that contributes to the observed loss of viability. Remarkably, the activity of protein kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining autoexcitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions.

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Section: Discussionsupporting

confidence: 69%

Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes

Kasler

Young

Mottet

et al. 2011

The Journal of Immunology

101

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“…On the other hand, p38 MAPK acts as an enhancer of myocyte apoptosis and cardiac pathologies and is believed to play a causative role in DCM in the cardiac stress responses. 58,59 It has been shown that gain of function of p38 MAPK in transgenic mice causes LV chamber dilation associated with reduced wall thickness, but no significant hypertrophy at the organ level, 60,61 consistent with the phenotype observed in Gab1-cKO mice under pressure overload. Taken together, our results suggest that dysregulation of the MAPK pathway could be the signaling mechanisms responsible for increased cardiomyocyte apoptosis and subsequent DCM observed in Gab1-cKO mice.…”

Section: Resultssupporting

confidence: 60%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that GabcKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti-and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure. The progression of heart failure is associated with cardiac remodeling, the changes of cardiac structure and function in response to various stress conditions such as pressure overload-generated hemodynamic stress and agingassociated oxidative stress. 1 Under hemodynamic stress, the heart undergoes a stage of compensated hypertrophy and then progresses into decompensated dilated cardiomyopathy (DCM) and heart failure. 2 Cardiac hypertrophy is an adaptive, regulatory process, in which activation of cardiomyocyte survival pathways maintains cardiac homeostasis against external stress. During the transition from compensatory hypertrophy to DCM, cardiomyocyte death plays a critical role in development of heart failure. [3][4][5][6] However, the molecular mechanisms for controlling the balance of cell survival and cell death during cardiac remodeling remain poorly understood.The Grb2-associated binder 1 (Gab1) is a member of the insulin receptor substrate-like multi-substrate docking protein family and expressed in various types of cells, including cardiomyocytes. [7][8][9] It is a central mediator of growth factor receptor signaling. 10,11 Gab1 is phosphorylated by tyrosine kinases, and then phosphorylated Gab1 recruits and activates phosphatidylinositol 3-kinase (PI3K)/Akt and protein tyrosine phosphatase SHP2 (PTPN11)/mitogen-activated protein kinase (MAPK...

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“…For example, in ␤ 2 -ARs-overexpressing transgenic mice with cardiomyopathy, cardiac-specific expression of dominant-negative p38␣ MAPK improved cardiac function and reduces cardiac apoptosis and fibrosis (5).…”

mentioning

confidence: 99%

A Novel Protein Kinase A-independent, β-Arrestin-1-dependent Signaling Pathway for p38 Mitogen-activated Protein Kinase Activation by β2-Adrenergic Receptors

Gong

et al. 2008

Journal of Biological Chemistry

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A growing body of evidence has demonstrated that p38 mitogen-activated protein kinase (MAPK) has a crucial role in various physiological and pathological processes mediated by ␤ 2 -adrenergic receptors (␤ 2 -ARs). However, the detailed mechanism of ␤ 2 -ARs-induced p38 MAPK activation has not yet been fully defined. The present study demonstrates a novel kinetic model of p38 MAPK activation induced by ␤ 2 -ARs in human embryonic kidney 293A cells. The ␤ 2 -AR agonist isoproterenol induced a time-dependent biphasic phosphorylation of p38 MAPK: the early phase peaked at 10 min, and was followed by a delayed phase that appeared at 90 min and was sustained for 6 h. Interestingly, inhibition of the cAMP/protein kinase A (PKA) pathway failed to affect the early phosphorylation but abolished the delayed activation. By contrast, silencing of ␤-arrestin-1 expression by small interfering RNA inhibited the early phase activation of p38 MAPK. Furthermore, the NADPH oxidase complex is a downstream target of ␤-arrestin-1, as evidenced by the fact that isoproterenol-induced Rac1 activation was also suppressed by ␤-arrestin-1 knockdown. In addition, early phase activation of p38 MAPK was prevented by inactivation of Rac1 and NADPH oxidase by pharmacological inhibitors, overexpression of a dominant negative mutant of Rac1, and p47 phox knockdown by RNA interference. Of note, we demonstrated that only early activation of p38 MAPK is involved in isoproterenol-induced F-actin rearrangement. Collectively, these data suggest that the classic cAMP/PKA pathway is responsible for the delayed activation, whereas a ␤-arrestin-1/Rac1/NADPH oxidase-dependent signaling is a heretofore unrecognized mechanism for ␤ 2 -AR-mediated early activation of p38 MAPK.

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Inhibition of p38α MAPK rescues cardiomyopathy induced by overexpressed β2-adrenergic receptor, but not β1-adrenergic receptor

Cited by 55 publications

References 42 publications

Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes

Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

A Novel Protein Kinase A-independent, β-Arrestin-1-dependent Signaling Pathway for p38 Mitogen-activated Protein Kinase Activation by β2-Adrenergic Receptors

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