title: Protective effects of intercalated disk protein afadin on chronic pressure overload-induced myocardial damage.
abstract: Adhesive intercellular connections at cardiomyocyte intercalated disks (IDs) support contractile force and maintain structural integrity of the heart muscle. Disturbances of the proteins at IDs deteriorate cardiac function and morphology. An adaptor protein afadin, one of the components of adherens junctions, is expressed ubiquitously including IDs. At present, the precise role of afadin in cardiac physiology or disease is unknown. To explore this, we generated conditional knockout (cKO) mice with cardiomyocyte-targeted deletion of afadin. Afadin cKO mice were born according to the expected Mendelian ratio and have no detectable changes in cardiac phenotype. On the other hand, chronic pressure overload induced by transverse aortic constriction (TAC) caused systolic dysfunction, enhanced fibrogenesis and apoptosis in afadin cKO mice. Afadin deletion increased macrophage infiltration and monocyte chemoattractant protein-1 expression, and suppressed transforming growth factor (TGF) β receptor signaling early after TAC procedure. Afadin also associated with TGFβ receptor I at IDs. Pharmacological antagonist of TGFβ receptor I (SB431542) augmented mononuclear infiltration and fibrosis in the hearts of TAC-operated control mice. In conclusion, afadin is a critical molecule for cardiac protection against chronic pressure overload. The beneficial effects are likely to be a result from modulation of TGFβ receptor signaling pathways by afadin.
authors.affiliation: Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Dimitar P
authors.initials: DP
authors.lastname: Zankov
authors.affiliation: Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Disease, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Tanaka-Okamoto
authors.affiliation: Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Disease, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Miyoshi
authors.affiliation: Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ogita
mesh_terms: D000818:Animals; D001011:Aorta / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism; D003251:Constriction, Pathologic; D005355:Fibrosis; D054143:Heart Failure, Systolic / Q000235:genetics*; D007365:Intercellular Junctions / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C108835:afadin