title: Mammalian enabled (Mena) is a critical regulator of cardiac function.
abstract: Mammalian enabled (Mena) of the Drosophila enabled/vasodilator-stimulated phosphoprotein gene family is a cytoskeletal protein implicated in actin regulation and cell motility. Cardiac Mena expression is enriched in intercalated discs (ICD), the critical intercellular communication nexus between adjacent muscle cells. We previously identified Mena gene expression to be a key predictor of human and murine heart failure (HF). To determine the in vivo function of Mena in the heart, we assessed Mena protein expression in multiple HF models and characterized the effects of genetic Mena deletion on cardiac structure and function. Immunoblot analysis revealed significant upregulation of Mena protein expression in left ventricle tissue from patients with end-stage HF, calsequestrin-overexpressing mice, and isoproterenol-infused mice. Characterization of the baseline cardiac function of adult Mena knockout mice (Mena(-/-)) via echocardiography demonstrated persistent cardiac dysfunction, including a significant reduction in percent fractional shortening compared with wild-type littermates. Electrocardiogram PR and QRS intervals were significantly prolonged in Mena(-/-) mice, manifested by slowed conduction on optical mapping studies. Ultrastructural analysis of Mena(-/-) hearts revealed disrupted organization and widening of ICD structures, mislocalization of the gap junction protein connexin 43 (Cx43) to the lateral borders of cardiomyoycytes, and increased Cx43 expression. Furthermore, the expression of vinculin (an adherens junction protein) was significantly reduced in Mena(-/-) mice. We report for the first time that genetic ablation of Mena results in cardiac dysfunction, highlighted by diminished contractile performance, disrupted ICD structure, and slowed electrical conduction.
authors.affiliation: Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Frédérick
authors.initials: F
authors.lastname: Aguilar
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Belmonte
authors.forename: Rashmi
authors.initials: R
authors.lastname: Ram
authors.forename: Sami F
authors.initials: SF
authors.lastname: Noujaim
authors.forename: Olga
authors.initials: O
authors.lastname: Dunaevsky
authors.forename: Tricia L
authors.initials: TL
authors.lastname: Protack
authors.forename: Jose
authors.initials: J
authors.lastname: Jalife
authors.forename: H
authors.initials: H
authors.lastname: Todd Massey
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
mesh_terms: D000818:Animals; D018031:Connexin 43 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D017629:Gap Junctions / Q000378:metabolism / Q000648:ultrastructure; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D010766:Phosphorylation
chemical_list: D018031:Connexin 43; D003598:Cytoskeletal Proteins; C511939:Enah protein, human; C102176:Enah protein, mouse; D008840:Microfilament Proteins