Abstract 17707: Gab1 Attenuates Angiotensin II-accelerated Atherosclerosis in Apolipoprotein E Deficient Mice via HGF/c-Met Signaling Pathway
Background and Aim: Atherosclerotic vascular disease is an inflammatory disease. Docking protein Gab1 has critical roles for biological effects of hepatocyte growth factor (HGF)/c-Met-dependent signaling pathway. We created endothelium-specific Gab1 knockout (Gab1ECKO) mice and reported that Gab1 is essential for postnatal angiogenesis via HGF/c-Met pathway in the last scientific session. We also demonstrated that Gab1 is required for activation of extracellular signal-regulated kinase (ERK) 1/2 (ERK1/2), ERK5 and AKT after stimulation with HGF in the human endothelial cells. However, the role of Gab1 in atherosclerotic vascular disease still remains elusive. The present study aims to test the hypothesis that Gab1 has vascular protective effects in the endothelium.
Methods and Results: Using DNA microarray, we searched for the downstream target of HGF/c-Met/Gab1 signaling pathway in human umbilical vein endothelial cells (HUVECs) and found that Kruppel-like factor 2 (KLF2) is upregulated through complex formation of Gab1 with tyrosine phosphatase SHP2 in response to HGF. HGF induced KLF2 upregulation through ERK5 in the HUVECs. In addition, we found that KLF2 mRNA expression is significantly decreased in the vascular endothelial cells of Gab1ECKO mice compared with control wild-type mice. Since KLF2 has been reported to play pivotal roles for maintenance of endothelium and anti-atherosclerosis, we examined the role of Gab1 for prevention of atherosclerosis through crossing Gab1ECKO mice with apolipoprotein E (apoE) knockout (apoEKO) mice. Six-month-old male apoEKO and apoEKO/Gab1ECKO mice fed a normal chow were treated with a 4-week infusion of angiotensin II (500 ng/min/kg) via a subcutaneously implanted osmotic infusion pump. After angiotensin II infusion, apoEKO/Gab1ECKO mice showed significant increases in atherosclerotic lesion area evaluated by Oil Red O staining, compared with apoEKO mice. Furthermore, both VCAM-1 expression and macrophage infiltration in the arterial wall was significantly enhanced in apoEKO/Gab1ECKO mice, compared with apoEKO mice.
Conclusion: These data indicate that Gab1 attenuates angiotensin II-accelerated atherosclerosis in apoEKO mice via HGF/c-Met signaling pathway.
- © 2010 by American Heart Association, Inc.