title: Mena associates with Rac1 and modulates connexin 43 remodeling in cardiomyocytes.
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.
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Rashmi
authors.initials: R
authors.lastname: Ram
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Wescott
authors.forename: Katherine
authors.initials: K
authors.lastname: Varandas
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018031:Connexin 43; C580592:Gja1 protein, rat; C586626:Mena protein, rat; D008840:Microfilament Proteins; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein
keywords: Mena; connexin 43; heart failure