Invited Speaker

Deficient Phosphorylation of P27 in Serine 10 is Associated with Human Atherosclerosis and Aggravates Disease Progression in Hypercholesterolemic Mice
Vicente Andres
Spain

The tumor suppressor p27 protects against murine atherosclerosis. Since phosphorylation of p27 at Serine 10 (S10) modulates its function and expression, we investigated the role of this post-translational modification in the development of atherosclerosis. We find markedly lower levels of p27-phospho-S10 in human atherosclerotic versus non-atherosclerotic arteries. Remarkably, both global and hematopoietic cell-specific expression of a non-phosphorylatable p27S10A mutant accelerates atherosclerosis in hypercholesterolemic apolipoprotein E-null mice without affecting plaque composition. We also find that, unlike the situation in other pathophysiological settings, expression of the p27S10A mutant does not affect arterial cell proliferation in advanced atheromas. Strikingly, p27S10A-apoE-null mice have a higher percentage of foam cells in peritoneal macrophage populations in vivo, which coincides with increased acetylated-LDL uptake by cultured p27S10A macrophages via a Rho/ROCK-dependent mechanism. p27S10A-apoE-null mice also exhibit increased expression of the proatherogenic cytokine MCP1 in atherosclerotic arteries and in LPS-stimulated macrophages. In conclusion, defective p27-phospho-S10 is associated with human atherosclerosis and accelerates disease progression in hypercholesterolemic apoE-null mice, at least in part through the enhancement of atherogenic properties of macrophages. Further studies are warranted to assess whether strategies aimed at increasing p27-phospho-S10 might inhibit atherosclerosis development.