Abstract 198: Angiotensin II Inhibits Cardiac Angiogenesis via the Cooperation of p53 and Jagged 1
It is well established that angiotension II (Ang II) is an important regulator in vascular homeostasis. Under certain conditions, Ang II could exert anti-angiogenic effects in cardiovascular system. However, the potential mechanism is unclear. P53 has been reported to suppress angiogenesis by promoting hypoxia-inducible factor-1 (Hif-1α) degradation. This study was conducted to determine the contribution of P53 and the underlying mechanism to the anti-angiogenic effect of Ang II. Angiogenesis was determined by tube formation from the cardiac microvascular endothelial cells (ECs). Microvessel density and cardiac function were analyzed in mice subjected to Ang II infusion (200 ng/kg/min ) or vehicle for 2 weeks. Ang II (1μM) greatly inhibited tube formation and stimulated phosphorylation and upregulation of P53 in cultured cardiac ECs. P53 inhibitor, pifithrin-α (PFT-α,3.0mg/kg), significantly reversed the inhibitory effect of Ang II on tube formation. Vascular endothelial growth factor (VEGF ) and Hif-1α has been reported as important pro-angiogenetic factors. The present study indicated that Ang II decreased VEGF concentration in cultured medium and downregulated Hif-1α expression in cultured ECs. Interestingly, Ang II also stimulated the upregulation of Jagged 1, a ligand of Notch, but it didn't affect the Delta-like 4 (Dll 4) , another ligand of Notch, expression in cardiac ECs. However, PFT-α partly abolished these effects of Ang II. These results were consistent with the study in vivo. Further research revealed that siRNA-Jagged 1 transfection in cultured ECs dramatically abolished the phosphorylation of P53 and the downregulation of Hif-1α induced by Ang II. Additionally, Ang II- induced inhibitory effect on capillary formation was blocked by siRNA-Jagged 1 transfection in cultured cardiac ECs. In conclusion, Ang II promoted the phosphorylation and upregulation of P53, and increased Jagged 1 expression, the upregulation of Jagged 1 in turn stimulated the phosphorylation of P53, which resulted in the downregulation of Hif-1α and VEGF, then induced the inhibitory effects of Ang II on capillary formation. The present data suggest that Ang II exerts anti-angiogenesis via the cooperation of P53 and Jagged 1 in vitro and in vivo.
- © 2012 by American Heart Association, Inc.