Abstract 20594: Rap1 is Activated by Vascular Injury and Elevated in Atherosclerosis and Regulates Vascular Smooth Muscle Cell Proliferation and Migration
Background: Rap1, a small GTPase member of Ras family, is expressed in vascular smooth muscle cells (VSMC) and functions in integrin-mediated cell adhesion and participates in vascular biology. Thrombin is concentrated at vascular injury site and elicits effects contributing to the progression of intimal hyperplasia and atherosclerosis. The mechanism of thrombin in modulating the response to vascular injury and atherosclerosis is not well understood. It is unknown whether Rap1 is activated or elevated by vascular injury and modulates thrombin-mediated vascular pathology.
Objectives: to investigate the effect of vascular injury on Rap1 activation and its expression in atherosclerosis in animal model. The effect of Rap1 on cell adhesion, proliferation, migration response to thrombin in VSMCs is evaluated.
Results: 3 days after balloon injury of rat carotid arteries, a significant increase in Rap1 activation was observed at the site of injury as compared to the contralateral normal arteries. Rap1 expression was increased in athersclerostic lesion in ApoE-deficient mice. In quiescent VSMCs, treatment with thrombin increased formation of activated Rap1. Overexpression of Rap1 specific GTPase-activating protein II (Rap1GAPII) by adenovirus not only obliterated the endogenous Rap1 activation, but also abrogated thrombin-elicited Rap1 activation in VSMCs. Overexpression of Rap1GAPII decreased SMC adhesion and spreading on fibronectin, inhibited the proliferatiion and migration effects of thrombin. Treatment with thrombin in VSMCs dramatically increased stress fiber formation and focal adhesion formation, and increased phosphorylation of integrin beta3, focal adhesion kinase (FAK), activation of p44/p42 MAP kinase and JNK1 activity in VSMCs, but all these effects were significantly prevented by overexpression of Rap1GAPII.
Conclusions: Rap1 activation is significantly increased by vascular injury in rat carotid artery, Rap1 expression is elevated in atherosclerostic lesion in ApoE-deficient mice suggesting it may play a role in intimal hyplerplasia and atherosclerosis development. Rap1 is activated by thrombin and regulates cell adhesion, spreading and proliferation, migration, and thrombin-induced signaling pathways in VSMCs.
Author Disclosures: H. Huang: None. J. Zeng: None. G. Zeng: None. J. Huang: None.
- © 2016 by American Heart Association, Inc.