Activation of DDR2 Involved in Atherosclerosis by Oxidative Stress

ABSTRACT

BACKGROUND: Reactive Oxygen species have been known to be a key factor to promote atherosclerosis. DDR2(Discoidin Domain Receptor 2) is a cell surface receptor tyrosine kinase which is activated by fiber collagen. Recently, DDR2 was suggested to be involved in activation of smooth muscle cell in blood vessel of atherosclerosis. METHODS: The effect of antioxidant, N-acetyl cysteine and H2O2(Hydrogen peroxide) in the activation of DDR2 by collagen was studied using HEK293 cells expressing DDR2. The direct activation of DDR2 tyrosine kinase domain by tyrosine phosphorylation upon the treatment of H2O2 was analysed after the kinase domain was expressed in sf9 cells. RESULTS: H2O2 enhanced DDR2 auto-phosphorylation and its cellular signaling to induce MMP-1 expression. However N-acetyl cysteine suppressed the DDR2 activation. The reactive oxygen induced tyrosine phosphorylation in DDR2 tyrosine kinase domain to activate its tyrosine kinase activity. CONCLUSIONS: DDR2 activity can be up-regulated by oxidative stress and this provides a mechanism that DDR2 plays a critical role when reactive oxygen species promote atherosclerosis. Therefore inhibition of the activated DDR2 could be a new therapeutic strategy for atherosclerosis.