Localization and characterization of a novel secreted protein, SCUBE2, in the development and progression of atherosclerosis.

Inhibition of atherosclerosis progression has long been the subject of intensive pathophysiologic investigations. The identification of a novel target molecule to redeem the cellular processes remains a major challenge in cardiology. Signal peptide CUB domain EGF-like repeat protein (SCUBE) family has been detected on human tissues and cultured cells. Two members of the SCUBE family, SCUBE1 and SCUBE3 are reported to play a role in cardiovascular diseases. The other member, SCUBE2 has been reported to mediate Hedgehog (Hh) protein signaling and is expressed in major blood vessels during mouse embryogenesis. However its involvement in cardiovascular diseases is not known yet. The aim of this study was to investigate SCUBE2 expression and localization in diffuse intimal thickening (DIT), an early event of atherosclerosis and in advanced lesion of atherosclerotic plaque. Carotid artery ligation in C57BL/6J mice was performed to induce intimal thickening, mimicking DIT in human. After 2 weeks of ligation, mRNA level of SCUBE2 increased significantly, while in LDLr-/- mice fed with high fat diet, a human atherosclerosis model, mRNA level of SCUBE2 expression markedly increased 8 weeks after start of the high fat diet. Our findings were confirmed by the observation of SCUBE2 expression in human coronary artery with DIT and advanced lesion of atherosclerotic plaque. Previous investigations described that SCUBE2 mediates Hh signaling pathway. We have observed that SCUBE2 expression is associated with Sonic Hedgehog (Shh) and its receptor, Patched (Ptc), both in DIT and advanced plaque lesion. Our results suggested that SCUBE2 is a new target molecule in atherosclerosis and might play an important role in atherosclerotic plaque progression via Hh signal transduction.