Endothelial Gab1 deletion accelerates angiotensin II-dependent vascular inflammation and atherosclerosis in apolipoprotein E knockout mice.
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.


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.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Kaori
K
Higuchi
Yoshikazu
Y
Nakaoka
Wataru
W
Shioyama
Yoh
Y
Arita
Takahiro
T
Hashimoto
Taku
T
Yasui
Kuniyasu
K
Ikeoka
Tadashi
T
Kuroda
Takashi
T
Minami
Keigo
K
Nishida
Yasushi
Y
Fujio
Keiko
K
Yamauchi-Takihara
Mikiyasu
M
Shirai
Naoki
N
Mochizuki
Issei
I
Komuro
D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins; D014657:Vasculitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; C490897:Gab1 protein, mouse; C498314:Klf2 protein, mouse; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D010750:Phosphoproteins; D000804:Angiotensin II