title: Akt-dependent Girdin phosphorylation regulates repair processes after acute myocardial infarction.
abstract: Myocardial infarction is a leading cause of death, and cardiac rupture following myocardial infarction leads to extremely poor prognostic feature. A large body of evidence suggests that Akt is involved in several cardiac diseases. We previously reported that Akt-mediated Girdin phosphorylation is essential for angiogenesis and neointima formation. The role of Girdin expression and phosphorylation in myocardial infarction, however, is not understood. Therefore, we employed Girdin-deficient mice and Girdin S1416A knock-in (Girdin(SA/SA)) mice, replacing the Akt phosphorylation site with alanine, to address this question. We found that Girdin was expressed and phosphorylated in cardiac fibroblasts in vitro and that its phosphorylation was crucial for the proliferation and migration of cardiac fibroblasts. In vivo, Girdin was localized in non-cardiomyocyte interstitial cells and phosphorylated in α-smooth muscle actin-positive cells, which are likely to be cardiac myofibroblasts. In an acute myocardial infarction model, Girdin(SA/SA) suppressed the accumulation and proliferation of cardiac myofibroblasts in the infarcted area. Furthermore, lower collagen deposition in Girdin(SA/SA) mice impaired cardiac repair and resulted in increased mortality attributed to cardiac rupture. These findings suggest an important role of Girdin phosphorylation at serine 1416 in cardiac repair after acute myocardial infarction and provide insights into the complex mechanism of cardiac rupture through the Akt/Girdin-mediated regulation of cardiac myofibroblasts.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hayano
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: takefuji@med.nagoya-u.ac.jp.
authors.forename: Mikito
authors.initials: M
authors.lastname: Takefuji
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Noda
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichimiya
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Asai
authors.affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006342:Heart Rupture, Post-Infarction / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D003094:Collagen; D008840:Microfilament Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins; C544013:alpha-smooth muscle actin, mouse; C527550:Ccdc88a protein, mouse
keywords: Akt; Cardiac fibroblast; Cardiac tissue rupture; Girdin; Myocardial infarction