Vascular calcification is a hallmark of atherosclerosis, a major cause of mortality and morbidity in the United States. Vascular smooth muscle cells (VSMC) contribute significantly to the development of atherosclerosis and vascular calcification. Emerging evidence supports the concept that vascular calcification resembles the process of osteogenesis. Increased oxidative stress and production of reactive oxygen species (ROS) accelerate the progression of atherosclerosis and vascular calcification. However, the molecular mechanisms underlying oxidative stress-induced vascular calcification have not been fully elucidated. Hydrogen peroxides (H2O2), a key ROS produced by vascular cells, has emerged as an important mediator of intracellular signaling. We found that H2O2 induced VSMC calcification in culture, featuring increased expression of "bone markers" and downregulation of "VSMC markers", concurrent with increased expression and enhanced activity of Runx2, and the key osteogenic transcription factor. Further, H2O2-induced VSMC calcification was inhibited in Runx2 deficient VSMC;while overexpression of Runx2 alone promoted VSMC calcification. Importantly, increased expression of Runx2 has been found in advanced atherosclerosis lesions, but not in normal vessels. Therefore, we conclude that Runx2 plays an important role in oxidative stress-induced vascular calcification. However, whether Runx2 expression contributes to onset or progression of atherosclerosis and vascular calcification is not known;and the mechanisms whereby Runx2 in regulating the process have not been defined. General Runx2 null mice and Runx2 C-terminal ablation mice are neonatal lethal due to defective bone formation, which precludes the characterization of the role of Runx2 in vascular calcification in vivo. In this proposal, we will generate a mouse model with SMC-specific ablation of Runx2 gene to determine the role of Runx2 in atherosclerosis and vascular calcification in vivo;and further elucidate Runx2-dependent molecular signals in regulating oxidative stress-induced vascular calcification. We hypothesize that oxidative stress induces Runx2 that is essential for vascular calcification.
Two Specific Aims will be pursued to test our hypothesis:
Aim 1 : Characterize Runx2 Dependent Vascular Calcification In Vivo. SMC-specific Runx2 ablation mice with apolipoprotein E deficiency background will be generated and used to characterize the role of Runx2 in the progression of atherosclerosis and vascular calcification in vivo.
Aim 2 : Define Runx2 Dependent Signals in Oxidative Stress-induced VSMC Calcification. Runx2-dependent stages during oxidative stress-induced VSMC calcification, Runx2 functional domains responsible for VSMC calcification and gene regulation;and Runx2-regualted molecular signals in H2O2-induced vascular calcification will be characterized. Understanding the function of Runx2 in regulating oxidative stress-induced vascular calcification will provide important insights into the development of novel strategies and targets for successful therapeutic interventions for atherosclerosis and vascular calcification.
Vascular calcification in atherosclerotic plaques is a prominent feature of atherosclerosis, a major cause of mortality and morbidity in the United States. We have demonstrated an essential role of Runx2 in vascular calcification in vitro. This proposal will further characterize role of Runx2 in vascular calcification in vivo and investigate the Runx2-regulated molecular signals in oxidative stress-induced vascular calcification. These studies will provide important molecular insights into understanding the pathogenesis of atherosclerosis, which will leads to development of novel strategy or drugs for atherosclerosis prevention or therapy. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page
|Tran, Ngoc-Tung; Su, Hairui; Khodadadi-Jamayran, Alireza et al. (2016) The AS-RBM15 lncRNA enhances RBM15 protein translation during megakaryocyte differentiation. EMBO Rep 17:887-900|
|Ma, Liping; Ambalavanan, Namasivayam; Liu, Hui et al. (2016) TLR4 regulates pulmonary vascular homeostasis and remodeling via redox signaling. Front Biosci (Landmark Ed) 21:397-409|
|Byon, Chang Hyun; Heath, Jack M; Chen, Yabing (2016) Redox signaling in cardiovascular pathophysiology: A focus on hydrogen peroxide and vascular smooth muscle cells. Redox Biol 9:244-253|
|Byon, Chang Hyun; Chen, Yabing (2015) Molecular Mechanisms of Vascular Calcification in Chronic Kidney Disease: The Link between Bone and the Vasculature. Curr Osteoporos Rep 13:206-15|
|Deng, Liang; Huang, Lu; Sun, Yong et al. (2015) Inhibition of FOXO1/3 promotes vascular calcification. Arterioscler Thromb Vasc Biol 35:175-83|
|Heath, Jack M; Sun, Yong; Yuan, Kaiyu et al. (2014) Activation of AKT by O-linked N-acetylglucosamine induces vascular calcification in diabetes mellitus. Circ Res 114:1094-102|
|Sun, Yong; Byon, Chang Hyun; Yuan, Kaiyu et al. (2012) Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ Res 111:543-52|
|Chen, Jianfeng; Yuan, Kaiyu; Mao, Xia et al. (2012) Serum response factor regulates bone formation via IGF-1 and Runx2 signals. J Bone Miner Res 27:1659-68|
|Mao, Xia; Debenedittis, Paige; Sun, Yong et al. (2012) Vascular smooth muscle cell Smad4 gene is important for mouse vascular development. Arterioscler Thromb Vasc Biol 32:2171-7|
|Byon, Chang Hyun; Sun, Yong; Chen, Jianfeng et al. (2011) Runx2-upregulated receptor activator of nuclear factor ÎºB ligand in calcifying smooth muscle cells promotes migration and osteoclastic differentiation of macrophages. Arterioscler Thromb Vasc Biol 31:1387-96|
Showing the most recent 10 out of 12 publications