Abstract 10031: Inhibition of Vascular Calcification in Smooth Muscle-Specific Runx2 Kockout Mice
Vascular calcification is a hallmark of atherosclerosis, a major cause of mortality and morbidity in the United States. We have previously reported that oxidative stress promotes calcification of vascular smooth muscle cells (VSMC) by an increased expression and transactivity of the osteogenic transcription factor Runx2. The present study determined the role of smooth muscle-expressed Runx2 in regulating vascular calcification using tissue-specific Runx2 ablation mice. Smooth muscle specific Runx2 ablation mice (ΔRunx2SMC) were generated by breeding Runx2 exon 8 floxed mice (Runx2f/f, provided by Dr. Javed A, UAB) with SM22α-Cre transgenic mice. The C-terminus of Runx2 encoded by exon 8 is critical for the osteogenic function of Runx2, because truncation of Runx2 exon 8 results in complete absence of bone formation and embryonic lethality. The ΔRunx2SMC mice were viable, fertile and exhibited normal growth phenotype. Histological analysis of cross sections of aorta from ΔRunx2SMC animals also did not reveal any difference in the gross anatomy and the expression of smooth muscle marker genes, including α-actin and SM22α. In vitro characterization of VSMC derived from ΔRunx2SMC mice confirmed that Runx2 ablation inhibited oxidative stress-induced VSMC calcification. To assess the function of Runx2 in the development of vascular calcification in vivo, ΔRunx2SMC mice were crossed with ApoE-/- mice, an established murine model for atherosclerosis and vascular calcification. The extent of high-fat diet-induced vascular calcification was markedly inhibited in ΔRunx2SMC;ApoE-/- mice compared with the control mice. The decrease in calcification was associated with the down-regulation of macrophage infiltration as well as RANKL expression. Moreover, macrophage infiltration was restricted to the endothelial layer in ΔRunx2SMCApoE-/- mice compared to primarily neointimal infiltration in control mice. These studies defined role of smooth muscle-expressed Runx2 in the pathogenesis of vascular calcification. Therefore, targeting Runx2 or Runx2 signals in VSMC may represent a novel strategy for prevention and therapy for vascular calcification.
- © 2011 by American Heart Association, Inc.