CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo

Passier, Robert; Zeng, Hong; Frey, Norbert; Naya, Francisco J.; Nicol, Rebekka; McKinsey, Timothy A.; Overbeek, Paul A.; Richardson, James A.; Grant, Stephen R.; Olson, Eric N.

doi:10.1172/jci8551

Cited by 463 publications

(409 citation statements)

References 71 publications

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“…Hypertrophic Signaling Dissociates the HDAC4⅐SRF Complex-Ca 2ϩ /CaMK-signaling is known to play an important role in transcription regulation of a large number of cardiac genes as well as in the induction and progression of hypertrophy (46). Given the role of SRF in the activation of cardiac muscle gene expression during hypertrophy, it was not surprising that association of SRF with a repressor, HDAC4, was regulated by Ca 2ϩ /CaMK signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Both SRF and HDAC4 have been previously shown to be substrates for CaMK-dependent phosphorylation (44,45). It has also been documented that CaMK signaling induces hypertrophy in cultured cardiac myocytes as well as in transgenic mice overexpressing a constitutively active form of CaMK-IV (46). To test whether CaMK-dependent phosphorylation of SRF and/or HDAC4 affects their binding abilities, we subjected both proteins to in vitro phosphorylation.…”

Section: Figmentioning

confidence: 99%

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Calcium/Calmodulin-dependent Protein Kinase Activates Serum Response Factor Transcription Activity by Its Dissociation from Histone Deacetylase, HDAC4

Davis

Gupta

Camoretti-Mercado

et al. 2003

Journal of Biological Chemistry

113

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Serum response factor (SRF) plays a pivotal role in cardiac myocyte development, muscle gene transcription, and hypertrophy. Previously, elevation of intracellular levels of Ca 2؉ was shown to activate SRF function without involving the Ets family of tertiary complex factors through an unknown regulatory mechanism. Here, we tested the hypothesis that the chromatin remodeling enzymes of class II histone deacetylases (HDAC4) regulate SRF activity in a Ca 2؉ -sensitive manner. Expression of HDAC4 profoundly repressed SRFmediated transcription in both muscle and nonmuscle cells. Protein interaction studies demonstrated physical association of HDAC4 with SRF in living cells. The SRF/ HDAC4 co-association was disrupted by treatment of cells with hypertrophic agonists such as angiotensin-II and a Ca 2؉ ionophore, ionomycin. Furthermore, activation of Ca 2؉ /calmodulin-dependent protein kinase (CaMK)-IV prevented SRF/HDAC4 interaction and derepressed SRF-dependent transcription activity. The SRF⅐HDAC4 complex was localized to the cell nucleus, and the activated CaMK-IV disrupted HDAC4/SRF association, leading to export of HDAC4 from the nucleus and stimulation of SRF transcription activity. Thus, these results identify SRF as a functional interacting target of HDAC4 and define a novel tertiary complex factor-independent mechanism for SRF activation by Ca 2؉ /CaMK-mediated signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Calcium/Calmodulin-dependent Protein Kinase Activates Serum Response Factor Transcription Activity by Its Dissociation from Histone Deacetylase, HDAC4

Davis

Gupta

Camoretti-Mercado

et al. 2003

Journal of Biological Chemistry

113

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“…On the other hand, FN induced calmodulin 1 (Supplemental Table S1), which activates calcineurin in response to elevated intracellular Ca 2ϩ levels. FN also induced the calcineurin binding protein myozenin 2 (calsarcin-1), which tethers calcineurin to the Z-line of sarcomeres (18), calcium/calmodulin-dependent protein kinase I, which synergizes with calcineurin in promoting hypertrophy (43), and frequenin homolog, which can substitute for calmodulin and regulate cardiac Ito K ϩ channels (38). It is possible that FN induces a permissive state for calcineurin activation but is insufficient for the full induction of calcineurin, which may require increased intracellular Ca 2ϩ levels induced by mechanical stretch or adrenergic agonists.…”

Section: Fibronectin-induced Cardiomyocyte Hypertrophymentioning

confidence: 99%

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

Chen

Huang

Stewart

et al. 2004

Physiological Genomics

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(FN) is an extracellular matrix protein that binds to integrin receptors and couples cardiac myocytes to the basal lamina. Cardiac FN expression is elevated in models of pressure overload, and FN causes cultured cardiac myocytes to hypertrophy by a mechanism that has not been characterized in detail. In this study, we analyzed the gene expression changes induced by FN in purified rat neonatal ventricular myocytes using the Affymetrix RAE230A microarray, to understand how FN affects gene expression in cardiac myocytes and to separate the effects contributed by cardiac nonmyocytes in vivo. Pathway analysis using z-score statistics and comparison with a mouse model of cardiac hypertrophy revealed several pathways stimulated by FN in cardiac myocytes. In addition to the known cardiac myocyte hypertrophy markers, FN significantly induced metabolic pathways including virtually all of the enzymes of cholesterol biosynthesis, fatty acid biosynthesis, and the mitochondrial electron transport chain. FN also increased the expression of genes coding for ribosomal proteins, translation factors, and the ubiquitin-proteasome pathway. Interestingly, cardiac myocytes plated on FN showed elevated expression of the fibrosis-promoting peptides connective tissue growth factor (CTGF), WNT1 inducible signaling pathway protein 2 (WISP2), and secreted acidic cysteine-rich glycoprotein (SPARC). Our data complement in vivo studies and reveal several novel genes and pathways stimulated by FN, pointing to cardiac myocyte-specific mechanisms that lead to development of the hypertrophic phenotype. extracellular matrix; integrin; ventricular remodeling; signal transduction; gene expression profiling OUTSIDE-IN SIGNALING CHARACTERIZES the cellular effects mediated by interaction of cellular receptors with the extracellular matrix. In neonatal rat ventricular myocytes (NRVM), clustering of integrin receptors induced by fibronectin (FN) (39,40) or RGD peptides (3) elicits a hypertrophic response, characterized by a 1.5-to 3-fold increase in cellular area and corresponding increases in global mRNA and protein synthesis, together with enhanced myofibrillogenesis and sarcomeric assembly. FN also induces increased formation of focal adhesions and costameres, which are sites of contact of extracellular matrix with integrins and associated cytoskeletal proteins associated with the Z-disks of the sarcomere (39). As in other models of hypertrophy, the hypertrophic response is accompanied by changes in gene expression, with increased expression of the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and fetal isoforms of sarcomeric proteins such as ␤-myosin heavy chain (␤MHC) and ␣-skeletal actin (␣SkA).The pathophysiological relevance of the FN-induced, integrin-mediated pathway is highlighted by the observation of increased deposition of FN in the extracellular matrix in animal models of cardiac hypertrophy and in patients with cardiac failure (5,20,22,29,42,45). The increased synthesis of FN is in part mediated...

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“…One of the factors whose genetic ablation causes morphological and transcriptional abnormalities during early cardiogenesis is MEF2C. It is a member of the small MEF2 family of MADS-box containing transcription factors that have been implicated in several fundamental processes including myogenesis, fibertype specification, cardiac hypertrophy, atherosclerosis, and as both an activator and inhibitor of apoptosis (Molkentin et al, 1995;Woronicz et al, 1995;Firulli et al, 1996;Kolodziejczyk et al, 1999;Mao et al, 1999;Youn et al, 1999;Okamoto et al, 2000;Passier et al, 2000;Wu et al, 2000;Dunn et al, 2001;Yan et al, 2001). Deletion of the mef2c gene results in a heart with a small, nonlooping LV, loss of the RV, no trabeculation, and decreased expression of several cardiac-specific genes (Lin et al, , 1998Bi et al, 1999;Bruneau et al, 2000;Liu et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

MEF2C is required for the normal allocation of cells between the ventricular and sinoatrial precursors of the primary heart field

Vong

Bi²,

O'Connor-Halligan

et al. 2006

Developmental Dynamics

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, and irx4 in outflow segment precursors of the primary heart field. In addition, the sinoatrial-enriched transcription factor, tbx5, was ectopically expressed in the primitive ventricle and ventricle-specific splicing of mef2b was lost, suggesting that the mutant ventricle had acquired atrial-specific characteristics. Collectively, these results suggest a fundamental role of MEF2C in ventricular cardiomyocyte differentiation and apportioning of cells between inflow and outflow precursors in the primary heart field.

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CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo

Cited by 463 publications

References 71 publications

Calcium/Calmodulin-dependent Protein Kinase Activates Serum Response Factor Transcription Activity by Its Dissociation from Histone Deacetylase, HDAC4

Calcium/Calmodulin-dependent Protein Kinase Activates Serum Response Factor Transcription Activity by Its Dissociation from Histone Deacetylase, HDAC4

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

MEF2C is required for the normal allocation of cells between the ventricular and sinoatrial precursors of the primary heart field

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