Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac ankyrin repeat protein (CARP) is a nuclear transcription cofactor that is activated by multiple signaling pathways in hypertrophic cardiac myocytes. Since CARP has been reported to be a transcriptional co-repressor, its activation during hypertrophy might contribute to the deregulation of gene expression leading to heart failure. Here, we found that alpha(1)-adrenergic signaling activates CARP mRNA expression in rat cardiac myocytes. To examine how alpha(1)-adrenergic signaling activates the CARP gene, a 660 bp fragment of the mouse CARP promoter was cloned. Previous reports suggested that the mouse CARP promoter was dependent on the GATA4 transcription factor whereas the human CARP promoter was dependent on transcriptional enhancer factor-1 (TEF-1). TEF-1 and GATA4 transcription factors, known mediators of alpha(1)-adrenergic signaling, bound to the mouse CARP promoter at several sites as determined by gel mobility shift assays. These sites are highly conserved between the mouse and human promoters, suggesting that they are functionally important in both. Mutation analysis showed that binding of TEF-1 factors is required for basal activity of the CARP promoter in cardiac myocytes. However, over-expression of TEF-1 factors could not potentiate the response of the CARP promoter to alpha(1)-adrenergic stimulation. On the other hand, the alpha(1)-adrenergic response was potentiated by GATA4 over-expression. Taken together, our results demonstrate that alpha(1)-adrenergic signaling regulates CARP expression in cardiac myocytes, in part through the transcription factor GATA4.
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PMID:Alpha(1)-adrenergic activation of the cardiac ankyrin repeat protein gene in cardiac myocytes. 1238 80

The cardiac ankyrin repeat domain 1 protein (ANKRD1, also known as CARP) has been extensively characterized with regard to its proposed functions as a cardio-enriched transcriptional co-factor and stress-inducible myofibrillar protein. The present results show the occurrence of alternative splicing by intron retention events in the pig and human ankrd1 gene. In pig heart, ankrd1 is expressed as four alternatively spliced transcripts, three of which have non-excised introns: ankrd1-contained introns 6, 7 and 8 (i.e., ankrd1-i6,7,8), ankrd1-contained introns 7 and 8 (i.e., ankrd1-i7,8), and ankrd1 retained only intron 8 (i.e., ankrd1-i8). In the human heart, two orthologues of porcine intron-retaining ankrd1 variants (i.e., ankrd1-i8 and ankrd1-i7,8) are detected. We demonstrate that these newly-identified intron-retaining ankrd1 transcripts are functionally intact, efficiently translated into protein in vitro and exported to the cytoplasm in cardiomyocytes in vivo. In the piglet heart, both the intronless and intron-retaining ankrd1 mRNAs are co-expressed in a chamber-dependent manner being more abundant in the left as compared to the right myocardium. Our data further indicate co-upregulation of the ankrd1 spliced variants in myocardium in the porcine model of diastolic heart failure. Most significantly, we demonstrate that in vivo forced expression of recombinant intronless ankrd1 markedly increases the levels of intron-retaining ankrd1 variants (but not of the endogenous main transcript) in piglet myocardium, suggesting that ANKRD1 may positively regulate the expression of its own intron-containing RNAs in response to cardiac stress. Overall, our findings demonstrate that in cardiomyocytes ANKRD1 can exist in multiple isoforms which may contribute to the functional diversity of this factor in heart development and disease.
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PMID:Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium. 1934 85

The Ankrd1 (ankyrin repeat domain 1) gene is known to be up-regulated in heart failure and acts as a co-activator of p53, modulating its transcriptional activity, but it remains inconclusive whether this gene promotes or inhibits cell apoptosis. In the present study, we attempted to investigate the role of Ankrd1 on AngII (angiotensin II)- or pressure-overload-induced cardiomyocyte apoptosis. In the failing hearts of mice with pressure overload, the protein expression of Ankrd1-encoded CARP (cardiac ankyrin repeat protein) was significantly increased. In NRCs (neonatal rat cardiomyocytes), AngII increased the expression of Ankrd1 and CARP. In the presence of AngII in NRCs, infection with a recombinant adenovirus containing rat Ankrd1 cDNA (Ad-Ankrd1) enhanced the mitochondrial translocation of Bax and phosphorylated p53, increased mitochondrial permeability and cardiomyocyte apoptosis, and reduced cell viability, whereas these effects were antagonized by silencing of Ankrd1. Intra-myocardial injection of Ad-Ankrd1 in mice with TAC (transverse aortic constriction) markedly exacerbated cardiac dysfunction with an increase in the lung weight/body weight ratio and a decrease in left ventricular fractional shortening. Cardiomyocyte apoptosis and the expression of phosphorylated p53 were also significantly increased in Ad-Ankrd1-infected TAC mice, whereas knockdown of Ankrd1 significantly inhibited the apoptotic signal pathway as well as cardiomyocyte apoptosis in pressure-overload mice. These findings indicate that overexpression of Ankrd1 exacerbates pathological cardiac dysfunction through enhancement of cardiomyocyte apoptosis mediated by the up-regulation of p53.
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PMID:Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents. 2551 Dec 37

The ankyrin repeat domain 1 (ANKRD1) protein is a cardiac-specific stress-response protein that is part of the muscle ankyrin repeat protein family. ANKRD1 is functionally pleiotropic, playing pivotal roles in transcriptional regulation, sarcomere assembly and mechano-sensing in the heart. Importantly, cardiac ANKRD1 has been shown to be highly induced in various cardiomyopathies and in heart failure, although it is still unclear what impact this may have on the pathophysiology of heart failure. This review aims at highlighting the known properties, functions and regulation of ANKRD1, with focus on the underlying mechanisms that may be involved. The current views on the actions of ANKRD1 in cardiovascular disease and its utility as a candidate cardiac biomarker with diagnostic and/or prognostic potential are also discussed. More studies of ANKRD1 are warranted to obtain deeper functional insights into this molecule to allow assessment of its potential clinical applications as a diagnostic or prognostic marker and/or as a possible therapeutic target.
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PMID:Ankyrin Repeat Domain 1 Protein: A Functionally Pleiotropic Protein with Cardiac Biomarker Potential. 2867 80