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: Shinji Hayano, Mikito Takefuji, Kengo Maeda, Tomonori Noda, Hitoshi Ichimiya, Koichi Kobayashi, Atsushi Enomoto, Naoya Asai, Masahide Takahashi, Toyoaki Murohara
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 88 Pg. 55-63 (Nov 2015) ISSN: 1095-8584 [Electronic] England
• PMID: 26393439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Actins
• Microfilament Proteins
• RNA, Small Interfering
• Vesicular Transport Proteins
• alpha-smooth muscle actin, mouse
• girdin protein, mouse
• Collagen
• Proto-Oncogene Proteins c-akt

Topics

• Actins (genetics, metabolism)
• Amino Acid Substitution
• Animals
• Animals, Newborn
• Cell Proliferation
• Collagen (genetics, metabolism)
• Gene Expression Regulation
• Gene Knock-In Techniques
• Heart Rupture, Post-Infarction (genetics, metabolism, mortality, pathology)
• Mice
• Mice, Knockout
• Microfilament Proteins (antagonists & inhibitors, genetics, metabolism)
• Myocardial Infarction (genetics, metabolism, mortality, pathology)
• Myocardium (metabolism, pathology)
• Myofibroblasts (metabolism, pathology)
• Phosphorylation
• Primary Cell Culture
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Signal Transduction
• Survival Analysis
• Vesicular Transport Proteins (antagonists & inhibitors, genetics, metabolism)