Abstract 5262: IP-10 in Renin-Angiotensin System Circuits Mediates Apoptosis and Senescence of Endothelial Cells
Angiotensin II promotes vascular inflammation that plays important roles in atherosclerosis. Leukocyte-endothelial interaction mediated by chemokines is a key step in vascular inflammation. In this study, we aimed to identify chemokines of which expression is regulated by angiotensin II in endothelial cells. We identified increased release of a CXC chemokine IP-10 from angiotensin II-stimulated human endothelial cells by an antibody array. Angiotensin II increased IP-10 expression in endothelium of coronary blood vessels in mice compared to control. Quantitative real-time PCR analysis revealed that angiotensin II significantly increased IP-10 mRNA expression in endothelial cells. Pretreatment with an AT1 receptor antagonist, valsartan, but not with an AT2 receptor antagonist, PD123319, blocked angiotensin II-induced IP-10 mRNA expression. IP-10 levels in conditioned media detected by ELISA increased in response to angiotensin II, which was blocked by the pretreatment with valsartan. These data indicate that angiotensin II stimulates IP-10 production from endothelial cells via AT1 receptors. In endothelial cells, IP-10 significantly increased mRNA expression of renin, angiotensin converting enzyme and angiotensinogen. Angiotensin II significantly increased mRNA expression of renin, angiotensin converting enzyme and angiotensinogen, which was blocked by IP-10 neutralization with antibody in endothelial cells. Angiotensin II levels in conditioned media were also increased by IP-10 compared to control. Angiotensin II-induced endothelial apoptosis recognized by DNA fragmentation was inhibited by IP-10 neutralization. Angiotensin II promoted endothelial cell senescence that is histochemically detectable by β-galactosidase staining, which was significantly prevented by IP-10 neutralization.These data indicate that IP-10 is involved not only in leukocyte-endothelial interaction but also in the circuit of angiotensin II-induced endothelial renin-angiotensin system activation that promotes endothelial apoptosis and senescence.