Mena associates with Rac1 and modulates connexin 43 remodeling in cardiomyocytes.

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  • Author(s): Ram R;Ram R;Ram R; Wescott AP; Varandas K; Dirksen RT; Blaxall BC
  • Source:
    American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2014 Jan 01; Vol. 306 (1), pp. H154-9. Date of Electronic Publication: 2013 Nov 01.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901228 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1539 (Electronic) Linking ISSN: 03636135 NLM ISO Abbreviation: Am J Physiol Heart Circ Physiol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Bethesda, Md. : American Physiological Society,
    • Subject Terms:
      Connexin 43/*metabolism ; Microfilament Proteins/*metabolism ; Myocytes, Cardiac/*metabolism ; rac1 GTP-Binding Protein/*metabolism; Actin Cytoskeleton/metabolism ; Animals ; Connexin 43/genetics ; Microfilament Proteins/genetics ; Myocytes, Cardiac/physiology ; Protein Binding ; Protein Transport ; Rats ; Rats, Sprague-Dawley ; Sarcolemma/metabolism ; rac1 GTP-Binding Protein/genetics
    • Abstract:
      Mena, a member of the Ena/VASP family of actin regulatory proteins, modulates microfilaments and interacts with cytoskeletal proteins associated with heart failure. Mena is localized at the intercalated disc (ICD) of adult cardiac myocytes, colocalizing with numerous cytoskeletal proteins. Mena's role in the maintainence of mechanical myocardial stability at the cardiomyocyte ICD remains unknown. We hypothesized that Mena may modulate signals from the sarcolemma to the actin cytoskeleton at the ICD to regulate the expression and localization of connexin 43 (Cx43). The small GTPase Rac1 plays a pivotal role in the regulation of actin cytoskeletal reorganization and mediating morphological and transcriptional changes in cardiomyocytes. We found that Mena is associated with active Rac1 in cardiomyocytes and that RNAi knockdown of Mena increased Rac1 activity significantly. Furthermore, Mena knockdown increased Cx43 expression and altered Cx43 localization and trafficking at the ICD, concomitant with faster intercellular communication, as assessed by dye transfer between cardiomyocyte pairs. In mice overexpressing constitutively active Rac1, left ventricular Mena expression was increased significantly, concomitant with lateral redistribution of Cx43. These results suggest that Mena is a critical regulator of the ICD and is required for normal localization of Cx43 in part via regulation of Rac1.
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    • Grant Information:
      R01-HL-089885 United States HL NHLBI NIH HHS; R01-HL-091475 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: Mena; connexin 43; heart failure
    • Accession Number:
      0 (Connexin 43)
      0 (Gja1 protein, rat)
      0 (Mena protein, rat)
      0 (Microfilament Proteins)
      EC 3.6.1.- (Rac1 protein, rat)
      EC 3.6.5.2 (rac1 GTP-Binding Protein)
    • Publication Date:
      Date Created: 20131105 Date Completed: 20140227 Latest Revision: 20211021
    • Publication Date:
      20231215
    • Accession Number:
      PMC3920153
    • Accession Number:
      10.1152/ajpheart.00749.2013
    • Accession Number:
      24186093