Abstract 14327: S100A4 Mediates Intimal Hyperplasia After Vascular Injury
Introduction: Vascular smooth muscle cell (VSMC) activations contribute to vascular remodeling. S100A4, a calcium-binding protein, mediates cancer cell proliferation and migration by interacting with the tumor suppressor p53 and with contractile proteins, respectively. Here we examined the role of S100A4 in intimal hyperplasia after vascular injury.
Methods and Results: Left carotid artery ligation was performed in wild type (Wt), S100a4 knockout (KO), and S100a4++eGFP reporter mice. Wt and S100a4++eGFP mice showed a marked intimal hyperplasia after ligation, where cells positive for GFP or for both S100A4 and smooth muscle α-actin were identified. Attenuated intimal hyperplasia was observed in KO mice compared to Wt (neointima/media; at 2 weeks KO 0.22±0.07 vs. Wt 0.88±0.33, and at 4 weeks KO 0.47±0.30 vs. Wt 0.99±0.36, p<0.05 respectively, n=12-20). In Wt mice, S100A4 expression was discernible in freshly-isolated aortas, but strongly increased in cultured mouse aortic VSMCs (mAoSMCs) treated with platelet-derived growth factor-BB (PDGF, 20 ng/ml). p53 was not detected in nuclei of Wt aortic media, and its DNA binding activity significantly decreased during PDGF stimulation in mAoSMCs (p53 activity relative to Wt aortas; 75±11%, n=4-5). In contrast, p53 was abundant in the nuclei of KO aortas, and its activity markedly increased in KO mAoSMCs stimulated with PDGF (117±16%, p<0.05 vs. Wt aortas and cells, n=4-5). PDGF-induced protrusion formation was diminished in KO mAoSMCs (number of protrusions; KO 0.8±0.1, p<0.05 vs. Wt 4.3±0.5, n=21-49). Proliferation and migration assays showed that siRNA knockdown or deficiency of S100a4 suppressed mAoSMC proliferation and migration induced by PDGF (siRNA in Wt cells; proliferation 62±12% and migration 35±20%, p<0.05 vs. control, respectively, n=5, and KO cells; proliferation 47±3% and migration 45±15%, p<0.05 vs. Wt cells, respectively, n=2-5).
Conclusions: S100A4 plays a crucial role in intimal hyperplasia following vascular injury via regulating VSMC proliferation and migration through controlling p53 activity and the protrusion machinery. Thus, S100A4 is a promising therapeutic target for the prevention of vascular remodeling such as atherosclerosis and restenosis following angioplasty.
- © 2013 by American Heart Association, Inc.