Andrew Cobb
King’s College, London
Title: Runx2-mediated calcification of vascular smooth muscle cells is dependent on genotoxic stress
Biography
Biography: Andrew Cobb
Abstract
Cardiovascular disease is a leading cause of mortality in developed nations. As ageing has established itself as one of the biggest causative factors of heart disease, we were interested in understanding what age-associated molecular changes were underlying these diseases. Hardening of the vascular network by ectopic calcification commonly occurs as we get older and this can lead to eventual heart failure and death. Accumulation of DNA damage and increased genomic instability are the primary drivers of ageing so we wanted to assess the impact of this upon calcification of vascular smooth muscle cells (VSMCs). Our data has shown induction of calcification with high calcium and phosphate in vitro causes increased levels of DNA damage in cells. Interestingly, addition of H2O2 to Ca+P media accelerated VSMC calcification and this was highly dependent on the presence of the osteogenic transcription factor Runx2 as its depletion attenuated this increase. Further analysis of Runx2 showed it localised to sites of DNA damage and its levels were significantly increased following DNA damage induction. We were able to determine a novel role for Runx2 in the regulation of H2AX phosphorylation on Ser139 via mediation of phosphorylation of an adjacent Tyrosine residue that is instrumental in determining cell fate following genotoxic stress. A side-effect of elevated Runx2 levels following DNA damage induction was subsequent enhanced binding of Runx2 to promoter regions of its target genes that are implicated in osteogenic differentiation, thereby explaining how DNA damage accelerates calcification of VSMCs. Importantly, we observed that inhibition of DNA damage response signalling was able to attenuate these effects and slow calcification.