Role of apelin in vascular smooth muscle cell phenotypic transition: a proatherogenic factor for atherosclerosis

Abstract Background. During atherosclerotic plaque formation smooth muscle cells (SMCs) switch from a contractile/differentiated to a synthetic/dedifferentiated phenotype We previously isolated differentiated spindle-shaped (S) and dedifferentiated rhomboid (R) SMCs from porcine coronary artery. R-SMCs express S100A4, a calcium binding protein. Aim. We investigated the role of apelin in this phenotypic conversion, as well as its relationship with S100A4. Results. We found that apelin was highly expressed in R-SMCs compared with S-SMCs. We observed a nuclear expression of apelin in SMCs within experimentally-induced intimal thickening of the porcine coronary artery and rat aorta. Plasmids targeting apelin to the nucleus (N. Ap) and to the secretory vesicles (S. Ap) were transfected into S-SMCs where apelin was barely detectable. Both plasmids induced the SMC transition towards a R-phenotype. Overexpression of N. Ap, and to a lesser degree S. Ap, led to a nuclear localization of S100A4. Stimulation of S-SMCs with platelet-derived growth factor-BB, known to induce the transition toward the R-phenotype, yielded nuclear expression of both apelin and S100A4. Conclusion. Apelin induces a SMC phenotypic transition towards the synthetic phenotype. These results suggest that apelin acts via nuclear re-localization of S100A4, raising the possibility of a new complex pro-atherogenic relationship between apelin and S100A4.