TRAIL Mediated Apoptosis Increases Carotid Plaque Vulnerability
Background: TRAIL, a TNF family protein, and its receptors DR 4 and 5 (TNF-R) are known to induce apoptosis in tumor cells via caspase activation. In this study, we examined the relationship between TRAIL, its effector caspases and apoptosis in carotid plaque (CP). Materials and Methods: Forty CPs were examined by immunohistochemistry, Western blotting and RNA protection assay for evidence of apoptosis (Tunel), TRAIL, caspase 3, 8 and PARP. We compared the expression of these pro-apoptotic proteins within plaque (P), and in areas of intimal thickening (IT) adjacent to the plaque to that of normal intima (N). Results: Apoptosis was detected in 10–25% of ECs, SMCs, macrophages and T lymphocytes in complex CP, but only in 1–3% SMCs in fibrous plaques. TRAIL and TNF-R, as well as caspases 3, 8, and PARP were present in all complex lesions. In N, there were focal areas of caspase 3 expression localized to ECs, whereas both caspase 3 and TRAIL were detected in all 3 regions of complex CP. There was a significant increase in the expression of TRAIL, TNF-R and caspase 8 in areas of IT compared to N (Fig. 1). Conclusions: The increased expression of TRAIL, TNF-R and caspases 3 and 8 in areas of IT and caspase 3 in ECs from N suggest that the mechanisms for ongoing EC injury and TRAIL-mediated cell death are present in complex CP. Modulation of these pro-apoptotic proteins and/or their inhibitors could potentially result in the introduction of therapeutic agents to attenuate plaque vulnerability.