1P274 15-deoxy-Δ12,14-prostaglandin J2 induces redifferentiation of cultured hwnan vascular smooth muscle cells through clusterin

To understand the mechanism of vascular smooth muscle cell (VSMC) differentiation is very important to clarify the pathogenesis of vascular diseases. In this study, we showed that 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2) induce almost complete redifferentiation from once dedifferentiated state in cultured human VSMCs. Compared to freshly isolated (differentiated) VSMCs, exponentially growing dedifferentiated VSMCS expressed much lower levels of contractile proteins, such as smooth muscle-myosin heavy chain (SM1 and SM2), calponin, h-caldesmon and a -smooth muscle actin. After addition of 15d-PGJ2 to quiescent VSMCS after confluent, cells gradually showed the "hill and valley" appearance and thereafter aggregated and formed nodules. Cells included in the nodules expressed high levels of SM2, the most specific VSMC differentiation marker expressed at a late stage of the differentiation as well as in medial VSMCS in vivo. We also examined the effect of 15d-PGJ2 on the expression of clusterin, a secreted protein that has been reported to induce nodular formation and differentiation of VSMCs, 15d-PGJ2 significantly increased the expression of clusterin mRNA and protein. Moreover, addition of an anti-clusterin antibody completely inhibited nodule formation induced by 15d-PGJ2. Our results suggested that 15d-PGJ2 induces differentiation of VSMCS probably by forming nodules through clusterin induction.