The role of RANTES as a crucial downstream cytokine in calcineurin-dependent VSMC apoptosis stimulated by INFgamma and CD40L.

ABSTRACT

Many studies have suggested that VSMC (vascular smooth muscle cell) apoptosis plays a key role in destabilization and rupture of atherosclerotic plaques. Therefore protection for VSMCs from apoptosis is a promising approach to stabilize 'vulnerable' lesions. However, the mechanisms as to why VSMCs in the fibrous cap often appear as profilerated in early stages, but turn apoptotic in advanced stages, are still unknown. In the present study, using RNAi (RNA interference) technology and a CaN (calcineurin) antagonist, the correlation between CaN and RANTES (regulated upon activation, normal T-cell expressed and secreted) in cultured rat apoptotic VSMCs stimulated by IFNgamma (interferon gamma; 20 ng/ml) and CD40L (CD40 ligand; 100 ng/ml) was investigated. RANTES released from VSMCs in each group was measured by ELISA and its mRNA in VSMCs was determined by RT (reverse transcription)-PCR. The total activity and expression of CaN in VSMCs were detected by the zymochemistry method and Western blot analysis respectively. From the results of the present study it can be hypothesized that an elevated CaN concentration in endochylema, by the CD40-CD40L signal pathway, induces VSMC apoptosis accomplished by the overexpression of RANTES. Therefore RANTES is a potential target for treating vulnerable atherosclerotic plaques owing to its crucial downstream regulating role in CaN-dependent VSMC apoptosis.