Endothelial Gab1 Deletion Accelerates Angiotensin II-Dependent Vascular Inflammation and Atherosclerosis in Apolipoprotein E Knockout Mice

Kaori Higuchi; Yoshikazu Nakaoka; Wataru Shioyama; Yoh Arita; Takahiro Hashimoto; Taku Yasui; Kuniyasu Ikeoka; Tadashi Kuroda; Takashi Minami; Keigo Nishida; Yasushi Fujio; Keiko Yamauchi-Takihara; Mikiyasu Shirai; Naoki Mochizuki; Issei Komuro

doi:10.1253/circj.CJ-11-1507

Vascular Biology and Vascular Medicine

Endothelial Gab1 Deletion Accelerates Angiotensin II-Dependent Vascular Inflammation and Atherosclerosis in Apolipoprotein E Knockout Mice

Kaori Higuchi, Yoshikazu Nakaoka, Wataru Shioyama, Yoh Arita, Takahiro Hashimoto, Taku Yasui, Kuniyasu Ikeoka, Tadashi Kuroda, Takashi Minami, Keigo Nishida, Yasushi Fujio, Keiko Yamauchi-Takihara, Mikiyasu Shirai, Naoki Mochizuki, Issei Komuro

Author information

Kaori Higuchi
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
Yoshikazu Nakaoka
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
Wataru Shioyama
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
Yoh Arita
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
Takahiro Hashimoto
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
Taku Yasui
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
Kuniyasu Ikeoka
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
Tadashi Kuroda
Department of Advanced Cardiovascular Therapeutics, Osaka University Graduate School of Medicine
Takashi Minami
Laboratory for Vascular Biology, Research Center for Advanced Science and Technology, University of Tokyo
Keigo Nishida
Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology
Yasushi Fujio
Department of Clinical Pharmacology and Pharmacogenomics, Osaka University Graduate School of Pharmaceutical Sciences
Keiko Yamauchi-Takihara
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
Mikiyasu Shirai
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute
Naoki Mochizuki
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute
Issei Komuro
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine

Keywords: Atherosclerosis, Endothelium, Grb2-associated binder 1 (Gab1), Inflammation, Krüppel-like factor (KLF)

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Supplementary material

2012 Volume 76 Issue 8 Pages 2031-2040

DOI https://doi.org/10.1253/circj.CJ-11-1507

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Abstract

Background: Docking protein Grb2-associated binder 1 (Gab1) has critical roles in signal transduction of various growth factors, cytokines, and numerous other molecules. Our previous reports show that Gab1 is essential for postnatal angiogenesis through the analysis of endothelium-specific Gab1 knockout (Gab1ECKO) mice. However, the role of Gab1 in atherosclerosis remains unknown. The aim of the present study was to elucidate the role of endothelial Gab1 in vascular inflammation and atherosclerosis. Methods and Results: We intercrossed Gab1ECKO mice with apolipoprotein E (ApoE) knockout (ApoEKO) mice. Six-month-old male ApoEKO/Gab1ECKO and littermate control (ApoEKO) mice were treated with angiotensin II (AngII) via an osmotic infusion mini-pump. After AngII treatment, ApoEKO/Gab1ECKO mice showed significantly enhanced atherosclerosis and aneurysm formation compared with control mice. The production of proinflammatory cytokines in the aorta was significantly enhanced in ApoEKO/Gab1ECKO mice compared with control mice. Furthermore, the expression levels of Krüppel-like factor (KLF) 2 (KLF2) and KLF4, key transcription factors for endothelial homeostasis, were significantly reduced in the aortic endothelium of ApoEKO/Gab1ECKO mice compared with those of control mice. Consistently, both vascular cell adhesion molecule-1 expression and macrophage infiltration on the aortic walls were enhanced in ApoEKO/Gab1ECKO mice compared with control mice. Conclusions: Collectively, endothelial Gab1 deletion accelerates AngII-dependent vascular inflammation and atherosclerosis on ApoE-null background presumably in association with downregulation of KLF2 and KLF4. (Circ J 2012; 76: 2031–2040)

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