RESUMO
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.
Assuntos
Apoptose , Ligante de CD40/farmacologia , Calcineurina/imunologia , Quimiocina CCL5/imunologia , Interferon gama/farmacologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Ligante de CD40/imunologia , Calcineurina/genética , Inibidores de Calcineurina , Células Cultivadas , Quimiocina CCL5/genética , Citocinas/genética , Citocinas/imunologia , Interferon gama/imunologia , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/imunologia , Interferência de RNA , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND AND AIMS: There is an imbalance between Th1 and Th2 in the development and progression of atherosclerosis and in patients with acute coronary syndrome (ACS) including acute myocardial infarction (AMI) and unstable angina. T helper cell type 3 (Th3), which primarily secretes transforming growth factor beta-1 (TGF-beta1), has been shown to inhibit both Th1 and Th2 cells. The present study was designed to investigate whether Th3 cells are involved in plaque destabilization and the onset of ACS. METHODS: Ninety one patients who underwent diagnostic catheterization were classified into four groups (AMI group, unstable angina group, stable angina group and chest pain syndrome group). The cell frequencies of Th1, Th2 and Th3 were detected using flow cytometry, and the concentrations of their related cytokines IFN-gamma, IL-4 and TGF-beta1 were studied by ELISA. RESULTS: Apart from the imbalance between Th1 and Th2, results revealed a significant decrease in peripheral Th3 number and levels of TGF-beta1 in patients with ACS as compared with those in patients with stable angina and chest pain syndrome (p<0.01). CONCLUSIONS: Downregulation of Th3 cells in patients with ACS may play a potential role in plaque destabilization and the onset of ACS.