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Hic-5 is required for fetal gene expression and cytoskeletal organization of neonatal cardiac myocytes.

ABSTRACT: Cardiac costameres link the extracellular matrix to the sarcomere at the z-disc and contain proteins such as integrins and other signaling molecules implicated in the regulation of pathological hypertrophy. Paxillin family members, hic-5 and paxillin, are scaffolding proteins associated with the integrin complex that have been shown to mediate numerous protein interactions in other cell types. While paxillin has been described in postnatal heart, hic-5 has not been identified. Our results provide evidence of hic-5 in neonatal cardiac myocytes co-localized with paxillin and alpha-actinin at the z-discs and the ends of actin filaments. Treatment with the hypertrophic agonist phenylephrine resulted in increased hic-5 expression while having no effect on paxillin levels. To see if increased hic-5 expression was sufficient to induce changes in cytoskeletal organization, hic-5 was overexpressed in myocytes by adenoviral infection. Hic-5 overexpression significantly increased the number of cells with organized cytoskeleton. Using siRNA mediated knockdown, we examined the requirement of hic-5 and paxillin in regulation of phenylephrine induced gene expression and cytoskeletal organization. Our results indicate that hic-5, not paxillin is required for upregulation of ANF and alpha-skeletal actin genes as well as in cytoskeletal reorganization. Finally, we demonstrated that hic-5 upregulation occurs downstream of MEK1/2-ERK1/2 signaling as inhibition of MEK1/2 using U0126 inhibitor completely inhibited hic-5 upregulation by PE. In a complimentary study, we showed that hic-5 knockdown had no effect on PE induced ERK1/2 phosphorylation. These findings demonstrate a novel role for hic-5 in the regulation of actin cytoskeleton and fetal gene expression.

SUBMITTER: Yund EE

PROVIDER: S-EPMC3427732 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Hic-5 is required for fetal gene expression and cytoskeletal organization of neonatal cardiac myocytes.

Yund Erin E EE Hill Joseph A JA Keller Rebecca S RS

Journal of molecular and cellular cardiology 20090618 4

Cardiac costameres link the extracellular matrix to the sarcomere at the z-disc and contain proteins such as integrins and other signaling molecules implicated in the regulation of pathological hypertrophy. Paxillin family members, hic-5 and paxillin, are scaffolding proteins associated with the integrin complex that have been shown to mediate numerous protein interactions in other cell types. While paxillin has been described in postnatal heart, hic-5 has not been identified. Our results provid ...[more]

PMID: 19540241

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Project description:Background Epigenetic modulators have been proposed as promising new drug targets to treat adverse remodeling in heart failure. Here, we evaluated the potential of 4 epigenetic drugs, including the recently developed histone deacetylase 6 (HDAC6) inhibitor JS28, to prevent endothelin-1 induced pathological gene expression in cardiac myocytes and analyzed the chromatin binding profile of the respective inhibitor targets. Methods and Results Cardiac myocytes were differentiated and puromycin-selected from mouse embryonic stem cells and treated with endothelin-1 to induce pathological gene expression (938 differentially expressed genes, q<0.05). Dysregulation of gene expression was at least in part prevented by epigenetic inhibitors, including the pan-BRD (bromodomain-containing protein) inhibitor bromosporine (290/938 genes), the BET (bromodomain and extraterminal) inhibitor JQ1 (288/938), the broad-spectrum HDAC inhibitor suberoylanilide hydroxamic acid (227/938), and the HDAC6 inhibitor JS28 (210/938). Although the 4 compounds were similarly effective toward pathological gene expression, JS28 demonstrated the least adverse effects on physiological gene expression. Genome-wide chromatin binding profiles revealed that HDAC6 binding sites were preferentially associated with promoters of genes involved in RNA processing. In contrast, BRD4 binding was associated with genes involved in core cardiac myocyte functions, for example, myocyte contractility, and showed enrichment at enhancers and intronic regions. These distinct chromatin binding profiles of HDAC6 and BRD4 might explain the different effects of their inhibitors on pathological versus physiological gene expression. Conclusions In summary, we demonstrated, that the HDAC6 inhibitor JS28 effectively prevented the adverse effects of endothelin-1 on gene expression with minor impact on physiological gene expression in cardiac myocytes. Selective HDAC6 inhibition by JS28 appears to be a promising strategy for future evaluation in vivo and potential translation into clinical application.

Dataset Information

Hic-5 is required for fetal gene expression and cytoskeletal organization of neonatal cardiac myocytes.

Publications

Hic-5 is required for fetal gene expression and cytoskeletal organization of neonatal cardiac myocytes.

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