Identification and expression of a novel isoform of cAMP response element modulator in the human heart

Müller, Frank; Boknı́k, Peter; Knapp, Jörg; Neumann, Joachim; Vahlensieck, Ute; Oetjen, Elke; Scheld, Hans H.; Schmitz, Wilhelm

doi:10.1096/fasebj.12.12.1191

Cited by 29 publications

(34 citation statements)

References 27 publications

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“…CREM can act as either a transcriptional activator or suppressor by interacting with CRE or CRE-like element. A transcriptional suppressor of CREM was identified in cardiac myocytes (15). Likewise, under these two conditions, we did not detect supershifted complexes after adding the anti-ATF3 antibody complexes formed with nuclear extracts from Ad.EGFP-infected cardiac myocytes (Fig.…”

Section: Fig 6 Atf3 Binds To Cre-like Element In the Plb Promotermentioning

confidence: 44%

Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3

Gao

Tang

Guo

et al. 2004

Journal of Biological Chemistry

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Cardiac-directed expression of adenylyl cyclase type VI (AC VI ) increases stimulated cAMP production, improves heart function, and increases survival in cardiomyopathy. In contrast, pharmacological agents that increase intracellular levels of cAMP have detrimental effects on cardiac function and survival. We wondered whether effects that are independent of cAMP might be responsible for these salutary outcomes associated with AC VI expression. We therefore conducted a series of experiments focused on how gene transcription is influenced by AC VI in cultured neonatal rat cardiac myocytes, with a particular focus on genes that might influence cardiac function. We found that overexpression of AC VI down-regulated mRNA and protein expression of phospholamban, an inhibitor of the sarcoplasmic reticulum Ca 2؉ -ATPase. We determined that the cAMPresponsive-like element in the phospholamban (PLB) promoter was critical for down-regulation by AC VI . Overexpression of AC VI did not alter the expression of CREB, CREM, ATF1, ATF2, or ATF4 proteins. In contrast, overexpression of AC VI increased expression of ATF3 protein, a suppressor of transcription. Following AC VI gene transfer, when cardiac myocytes were stimulated with isoproterenol or NKH477, a water-soluble forskolin analog that directly stimulates AC, expression of ATF3 protein was increased even more, which correlated with reduced expression of PLB. We then showed that AC VI -induced ATF3 protein binds to the cAMP-responsive-like element on the PLB promoter and that overexpression of ATF3 in cardiac myocytes inhibits PLB promoter activity. These findings indicate that AC VI has effects on gene transcription that are not directly dependent on cAMP generation. Adenylyl cyclase (AC)1 is the effector molecule in the ␤-adrenergic receptor-G-protein-AC signaling pathway in cardiac myocytes and other cells. Previous studies showed that the amount of AC sets a limit on the ability of cardiac myocytes to generate cAMP (1), and cardiac-directed expression of AC type VI (AC VI ) has pronounced favorable effects on cardiovascular function in normal and failing hearts (2-6).The mechanisms explaining these favorable effects of AC VI are not precisely known. The most direct explanation is that the benefits stem from increased intracellular levels of cAMP; this explanation is contrary to current dogma in heart failure which asserts that inotropic agents that increase cAMP are bad for the heart. Indeed, pharmacological agents that stimulate the ␤-adrenergic receptor or decrease the breakdown of cAMP increase cardiac function but do not appear to prolong life (7-9). In contrast, AC VI , a dominant AC isoform in mammalian cardiac myocytes, improves global cardiac function, attenuates myocardial hypertrophy, and increases survival in murine cardiomyopathy (3, 4). However, when cardiac-directed ␤-adrenergic receptor expression is used to treat this same model, life is shortened (10), underscoring the marked differences evoked by these signaling elements, both of which are associated w...

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Section: Fig 6 Atf3 Binds To Cre-like Element In the Plb Promotermentioning

confidence: 44%

Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3

Gao

Tang

Guo

et al. 2004

Journal of Biological Chemistry

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“…48. Immunological detection was performed using polyclonal antibodies against AP-2aA (1 : 500; Santa Cruz, CA, USA) and CSQ 49 (1 : 2000; kindly provided by Dr. LR Jones, Indianapolis, USA).…”

Section: Protein Analysismentioning

confidence: 99%

Transcription factor AP-2α triggers apoptosis in cardiac myocytes

et al. 2004

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Idiopathic-dilated cardiomyopathy (IDC) is a common primary myocardial disease of unknown etiology associated with apoptosis, cardiac dilatation, progressive heart failure and increased mortality. An elevation of the transcription factor activator protein 2a (AP-2a) is involved in vertebrate embryonic development and oncogenesis. Here, we show that AP-2a protein is expressed in the human heart and increased in human failing myocardium with IDC. Adenovirusmediated overexpression of human AP-2a triggered apoptosis and increased mRNA levels of Bcl-2 family members Bax and Bcl-x in rat cardiomyocytes. Immunohistological analysis of human myocardium revealed an increased percentage of AP-2a-positive nuclei in IDC and, interestingly, a colocalization of AP-2a-positive but not -negative cells with a caspasecleaved fragment of poly(ADP-ribose)polymerase. We suggest AP-2a as a novel cardiac regulator implicated in the activation of apoptosis in IDC.

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“…However, mechanisms underlying the altered gene regulation in failing hearts including alterations associated with ion channel remodeling are not known in detail. The transcription factors of the cAMP response element binding protein/modulator and activating transcription factor 1 (CREB/CREM/ ATF1) family are expressed in the heart (25,26) and mediate the regulation of gene transcription in response to cAMP by binding to cAMP responsive elements (CREs, TGACGTCA, and variants thereof) in the promoter region of target genes (for review, see Ref. 23).…”

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confidence: 99%

CREB critically regulates action potential shape and duration in the adult mouse ventricle

Schulte

Seidl

Nunes

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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FU. CREB critically regulates action potential shape and duration in the adult mouse ventricle. Am J Physiol Heart Circ Physiol 302: H1998 -H2007, 2012. First published March 16, 2012; doi:10.1152/ajpheart.00057.2011The cAMP response element binding protein (CREB) belongs to the CREB/ cAMP response element binding modulator/activating transcription factor 1 family of cAMP-dependent transcription factors mediating a regulation of gene transcription in response to cAMP. Chronic stimulation of ␤-adrenergic receptors and the cAMP-dependent signal transduction pathway by elevated plasma catecholamines play a central role in the pathogenesis of heart failure. Ion channel remodeling, particularly a decreased transient outward current (Ito), and subsequent action potential (AP) prolongation are hallmarks of the failing heart. Here, we studied the role of CREB for ion channel regulation in mice with a cardiomyocyte-specific knockout of CREB (CREB KO). APs of CREB KO cardiomyocytes were prolonged with increased AP duration at 50 and 70% repolarization and accompanied by a by 51% reduction of I to peak amplitude as detected in voltageclamp measurements. We observed a 29% reduction of Kcnd2/Kv4.2 mRNA in CREB KO cardiomyocytes mice while the other I to-related channel subunits Kv4.3 and KChIP2 were not different between groups. Accordingly, Kv4.2 protein was reduced by 37% in CREB KO. However, we were not able to detect a direct regulation of Kv4.2 by CREB. The I to-dependent AP prolongation went along with an increase of I Na and a decrease of ICa,L associated with an upregulation of Scn8a/Nav1.6 and downregulation of Cacna1c/Cav1.2 mRNA in CREB KO cardiomyocytes. Our results from mice with cardiomyocyte-specific inactivation of CREB definitively indicate that CREB critically regulates the AP shape and duration in the mouse ventricle, which might have an impact on ion channel remodeling in situations of altered cAMP-dependent signaling like heart failure. ion channel remodeling; heart; transcriptional regulation; adenosine 3=,5=-cyclic monophosphate response element binding protein; transient outward current

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Identification and expression of a novel isoform of cAMP response element modulator in the human heart

Cited by 29 publications

References 27 publications

Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3

Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3

Transcription factor AP-2α triggers apoptosis in cardiac myocytes

CREB critically regulates action potential shape and duration in the adult mouse ventricle

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