The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

Muñoz, Juan Pablo; Collao, Andres; Chiong, Mario; Maldonado, Carola; Adasme, Tatiana; Carrasco, Loreto; Ocaranza, Paula; Bravo, Roberto; González, López; Díaz‐Araya, Guillermo; Hidalgo, Cecilia; Lavandero, Sergio

doi:10.1016/j.bbrc.2009.07.147

Cited by 43 publications

(46 citation statements)

References 28 publications

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“…In a similar way, a distribution of the IGF-1R in lipid rafts/caveolae has been described as necessary for adipocyte differentiation, 23 and IGF-1 is indeed an essential factor regulating not only cardiac myocyte differentiation 36 but also hypertrophy in pathological models where embryonic gene programs are reactivated. 37 The role of T-tubules in nuclear signaling may also have important ramifications for disease states, such as heart disease or ischemia, when T-tubules are reduced, swollen, or otherwise dysfunctional. 38 The IGF-1R signaling pathways are known to promote cardiac growth, improve cardiac contractility, prevent cardiac myocyte apoptosis, and contribute to cardiac metabolic adaptability.…”

Section: +mentioning

confidence: 99%

Local Control of Nuclear Calcium Signaling in Cardiac Myocytes by Perinuclear Microdomains of Sarcolemmal Insulin-Like Growth Factor 1 Receptors

Ibarra

Vicencio

Estrada

et al. 2013

Circulation Research

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Artículo de publicación ISIRationale: The ability of a cell to independently regulate nuclear and cytosolic Ca2+ signaling is currently attributed to the differential distribution of inositol 1,4,5-trisphosphate receptor channel isoforms in the nucleoplasmic versus the endoplasmic reticulum. In cardiac myocytes, T-tubules confer the necessary compartmentation of Ca2+ signals, which allows sarcomere contraction in response to plasma membrane depolarization, but whether there is a similar structure tunneling extracellular stimulation to control nuclear Ca2+ signals locally has not been explored. Objective: To study the role of perinuclear sarcolemma in selective nuclear Ca2+ signaling. Methods and Results: We report here that insulin-like growth factor 1 triggers a fast and independent nuclear Ca2+ signal in neonatal rat cardiac myocytes, human embryonic cardiac myocytes, and adult rat cardiac myocytes. This fast and localized response is achieved by activation of insulin-like growth factor 1 receptor signaling complexes present in perinuclear invaginations of the plasma membrane. The perinuclear insulin-like growth factor 1 receptor pool connects extracellular stimulation to local activation of nuclear Ca2+ signaling and transcriptional upregulation through the perinuclear hydrolysis of phosphatidylinositol 4,5-biphosphate inositol 1,4,5-trisphosphate production, nuclear Ca2+ release, and activation of the transcription factor myocyte-enhancing factor 2C. Genetically engineered Ca2+ buffers—parvalbumin—with cytosolic or nuclear localization demonstrated that the nuclear Ca2+ handling system is physically and functionally segregated from the cytosolic Ca2+ signaling machinery. Conclusions: These data reveal the existence of an inositol 1,4,5-trisphosphate–dependent nuclear Ca2+ toolkit located in direct apposition to the cell surface, which allows the local control of rapid and independent activation of nuclear Ca2+ signaling in response to an extracellular ligan

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Section: +mentioning

confidence: 99%

Local Control of Nuclear Calcium Signaling in Cardiac Myocytes by Perinuclear Microdomains of Sarcolemmal Insulin-Like Growth Factor 1 Receptors

Ibarra

Vicencio

Estrada

et al. 2013

Circulation Research

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“…The encoded protein, MEF2 polypeptide C, is activated by IGF1 and participates in IGF1-induced cardiac hypertrophy through p38-MAPK phosphorylation (1). However, the exact role of MEF2C on global IGF1 signaling is unknown (18). DUSP4 encodes a member of the dual specificity protein phosphatase subfamily, which dephosphorylates both phosphothreonine and phosphotyrosine residues in MAPKs, inactivates MAPK signaling, and thereby inhibits cellular proliferation (19).…”

Section: Discussionmentioning

confidence: 99%

Post-receptor IGF1 insensitivity restricted to the MAPK pathway in a Silver–Russell syndrome patient with hypomethylation at the imprinting control region on chromosome 11

Montenegro

Leal²,

Coutinho³

et al. 2012

European Journal of Endocrinology

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Background: Hypomethylation of the paternal imprinting center region 1 (ICR1) is the most frequent molecular cause of Silver-Russell syndrome (SRS). Clinical evidence suggests that patients with this epimutation have mild IGF1 insensitivity. Objective: To assess in vitro IGF1 action in fibroblast culture from a patient with SRS and IGF1 insensitivity. Methods: Fibroblast cultures from one patient with SRS due to ICR1 demethylation and controls were established. The SRS patient has severe growth failure, elevated IGF1 level, and poor growth rate during human recombinant GH treatment. IGF1 action was assessed by cell proliferation, AKT, and p42/44-MAPK phosphorylation. Gene expression was determined by real-time PCR. Results: Despite normal IGF1R sequence and expression, fibroblast proliferation induced by IGF1 was 50% lower in SRS fibroblasts in comparison with controls. IGF1 and insulin promoted a p42/44-MAPK activation in SRS fibroblasts 40 and 36%, respectively, lower than that in control fibroblasts. On the other hand, p42/44-MAPK activation induced by EGF stimulation was only slightly reduced (75% in SRS fibroblasts in comparison with control), suggesting a general impairment in MAPK pathway with a greater impairment of the stimulation induced by insulin and IGF1 than by EGF. A PCR array analysis disclosed a defect in MAPK pathway characterized by an increase in DUSP4 and MEF2C gene expressions in patient fibroblasts. Conclusion: A post-receptor IGF1 insensitivity was characterized in one patient with SRS and ICR1 hypomethylation. Although based on one unique severely affected patient, these results raise an intriguing mechanism to explain the postnatal growth impairment observed in SRS patients that needs confirmation in larger cohorts.

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“…Their activation triggers downstream signaling through pathways including the MEK-ERK pathway and the PI3K pathway via their own PTK activity, or via their interaction with and activation of the EGFR family receptors (229,230). IGF alone is able to induce hypertrophic growth in cultured cardiomyocytes (231)(232)(233). Mice overexpressing PDGF develop significant cardiac hypertrophy (234), supporting the prohypertrophic role of these receptors and their ligands.…”

Section: 22mentioning

confidence: 97%

Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets?

Wang¹,

Bosonea²,

Odenbach³

et al. 2012

CHYR

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Hypertension, the condition characterized by sustained elevated blood pressure, affects over 25% of adults in developed countries and is accompanied by pathological cardiac remodeling (i.e., hypertrophy and fibrosis), thus being a major risk factor for cardiac failure. Life style, the environment, genetic factors, diabetes or obesity can all promote development and progression of hypertension associated cardiovascular disease in part because these conditions induce an excess production of pro-hypertensive, pro-hypertrophic and pro-fibrotic agonists.Here we review signaling pathways shared by major agonists including angiotensin II, catecholamines and endothelins. At the cellular level, these agonists initiate disease signaling by activating cognate G protein-coupled receptors (GPCRs). Early events in agonist-signaling include Ca 2+ release from intracellular stores, Ca 2+ uptake from extracellular millieu into cells and reactive oxygen species (ROS) generation by NADPH oxidase. ROS production in turn contributes to activation of matrix metalloproteinases (MMPs) and 'a disintegrin and metalloproteinases' (ADAMs). Activated MMPs and ADAMs cleave growth factors, cytokines as well as cell surface receptors, including GPCRs. Excessive activation of MMPs and ADAMs links agonist receptors with transcription and translation of disease-associated genes, including those of MMPs and ADAMs. Recent research indicates a complex and dynamic regulation of MMPs and ADAMs activity and expression by agonists, which poses a significant challenge to strategies aiming at targeting specific MMPs or ADAMs in cardiovascular disease.

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The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

Cited by 43 publications

References 28 publications

Local Control of Nuclear Calcium Signaling in Cardiac Myocytes by Perinuclear Microdomains of Sarcolemmal Insulin-Like Growth Factor 1 Receptors

Local Control of Nuclear Calcium Signaling in Cardiac Myocytes by Perinuclear Microdomains of Sarcolemmal Insulin-Like Growth Factor 1 Receptors

Post-receptor IGF1 insensitivity restricted to the MAPK pathway in a Silver–Russell syndrome patient with hypomethylation at the imprinting control region on chromosome 11

Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets?

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