The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice

Bueno, Orlando F.; Windt, León J. De; Tymitz, Kevin; Witt, Sandra A.; Kimball, Thomas R.; Klevitsky, Raisa; Hewett, Timothy E.; Jones, Steven P.; Lefer, David J.; Peng, Chang Fu; Kitsis, Richard N.; Molkentin, Jeffery D

doi:10.1093/emboj/19.23.6341

Cited by 722 publications

(581 citation statements)

References 55 publications

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“…The ERK-1/2 signaling was shown to promote adaptive hypertrophy with normalized wall stress and compensation for increased load. 30,31 Our study documented that R-568 increased ERK-1/2 activation. As the LVH was unaltered, one might argue that the treatment did not prevent the cardiac hypertrophy but shifted the signaling toward adaptive growth instead of fibrosis.…”

Section: Discussionmentioning

confidence: 53%

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Koleganova

Piecha

Ritz

et al. 2009

Laboratory Investigation

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In patients with chronic renal failure, the heart undergoes remodeling, characterized by hypertrophy, fibrosis, and capillary/myocyte mismatch. In this study, we observed the effects of the calcimimetic agent R-568 on microvascular disease and interstitial fibrosis of the heart. Three-month-old male Sprague-Dawley rats were randomized to subtotal nephrectomy (SNX) or sham operation and subsequently received vehicle or R-568 under two experimental protocols, one for 1 month and the other for 3 months. Echocardiography, capillary length density, volume density of interstitial tissue, and immunohistochemistry and western blots (calcium-sensing receptor, collagen I and III, transforming growth factor (TGF)-b, mitogen-activated protein kinases, and nitrotyrosine) were assessed. After SNX, weight and wall thickness of the left and the right ventricle were elevated. The ratio of heart to body weight and interventricular septum thickness were not changed by R-568 treatment. The left ventricle fractional shortening (by echocardiography) was lower in SNX; this was ameliorated by R-568. Reduced capillary length density and increased interstitial fibrosis in SNX were improved by R-568, which also reduced the expression of TGF-b, and collagen I and III. The calcimimetic increased the activation of ERK-1/2, normalized p38 and JNK signaling, and prevented oxidative stress. We conclude that lowering parathyroid hormone with a calcimimetic significantly improves cardiac histology and function but not the left ventricular mass in SNX.

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Section: Discussionmentioning

confidence: 53%

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Koleganova

Piecha

Ritz

et al. 2009

Laboratory Investigation

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show abstract

“…In this study, we found that ERK1/2 phosphorylation significantly decreased but p38MAPK phosphorylation increased in Gab1-cKO mice compared with Gab1-WT mice under pressure overload. ERK1/2 phosphorylation is associated with concentric LV hypertrophy without signs of progression toward heart failure, 54 and is thought to be a component of an consequential adaptive mechanism in the myocardium. 55 The blunting of the ERK1/2 signaling using a dominant-negative Raf1 blocks adaptive cardiac hypertrophy, accompanied by an increase in apoptosis, and LV dysfunction, concluding with an enhancement in mortality rate when subjected to pressure overload.…”

Section: Resultsmentioning

confidence: 99%

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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“…Mitogen‐activated protein kinases (MAPKs) and, especially, extracellular signal‐regulated kinase (ERK), which is activated by virtually all hypertrophic stimuli in cardiomyocytes, represent the central pathway regulating transcription of ANP and BNP 17. Constitutive activation of MEK1 (upstream activator of ERK) in myocytes induces cardiac hypertrophy and NP expression,18 but loss of ERK from cardiomyocytes is not sufficient to block stress‐induced hypertrophic response 19. In addition to ERK, p38 MAPK has been shown to regulate NP expression in primary cardiomyocyte culture.…”

Section: Regulation Of Anp and Bnp Gene Expressionmentioning

confidence: 99%

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

Kerkelä

Ulvila

Magga

2015

JAHA

127

108

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The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice

Cited by 722 publications

References 55 publications

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

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

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

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