Impact of human Tp53 Arg72Pro polymorphism on endothelial progenitor cell mobilization and functional recovery after intracerebral hemorrhage

Resumen del trabajo presentado al XXXXVIII Congreso de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Valencia del 7 al 10 de septiembre de 2015.
Differences in genetic susceptibility to apoptosis account for the different functional recovery on stroke patients. Recently, we described that Tp53 Arg72Pro single nucleotide polymorphism (SNP) is associated with functional prognosis in patients after intracerebral hemorrhage (ICH). There is also evidence of a benefi cial effect of endothelial progenitor cell (EPC) mobilization and neovascularization through growth factor signaling, such as VEGF and SDF-1a, in brain repair after ischemia. To elucidate the mechanisms underlying this phenomenon, we have used the collagenase ICH model in two groups of knock-in (KI) mice each one carrying a humanized allele of the Tp53 gene (Arg72 and Pro72). By immunohistochemical analysis at different times (6h, 1, 7 and 14 days) after experimental ICH, we studied the pattern of cell death. Also VEGF and SDF-1a serum levels and the number of CD34+/VEGFR2+ (EPC) cells were determined by ELISA and fl ow cytometry, respectively. We found that neuronal apoptosis was higher in Arg72 KI mice than in Pro72 animals, from 24 h up to day seven, as revealed by NeuN-TUNEL co-staining. Furthermore, mice carrying the Pro72 polymorphic variant showed higher VEGF and SDF-1a serum levels and a enhanced number of circulating EPCs after ICH than those with the Arg72 variant. Our results indicate that the Arg72 polymorphic variant is accountable for a higher level of apoptosis in the brain of rodents under experimental ICH. Arg72Pro SNP also modulates VEGF and SDF-1a release and, subsequently, EPC mobilization after ICH, which may account for the different brain repair. In conclusion, the human Tp53 Arg72Pro polymorphism controls functional outcome and recovery after ICH.
Funded by ISCIII (PI12/0685; RD12/0014/0007; RD12/0014/0001), FEDER.