Proposed TNF-α signaling during aneurysm growth and rupture. TNF-α interaction with TNFR1 and TNFR2 elicits either inflammation/survival or apoptosis by recruiting different adaptor proteins. Recruitment of FADD and TRADD leads to activation of apoptosis while recruitment of RIP and TRAF2 generates NFκB, initiating inflammation. During early stages of aneurysm development, membrane bound TNF interacts with TNFR2 and initiates EC activation. The threshold of membrane bound TNF-α appears to control EC activation and survival. While lower TNF-α expression would be expected to activate EC, higher TNF-α concentration would cause EC dysfunction and a fraction of EC death. However, the majority of EC/SMC apoptosis would occur when soluble TNF-α interacts with TNFR1 (present on EC and SMC) (Norwak et al 2000). The threshold of soluble TNF-α is critical, as lower concentration would increase SMC proliferation, which might stabilize aneurysms from rupturing (stable aneurysms) (Fig. 4). On the other hand, sustained TNF-α might activate MMPs and other calcium dependent proteases such as calpain promoting aneurysm rupture.
Abbreviations: TNFR, Tumor necrosis factor receptor; FADD, Fas associated death domain; TRADD, TNF receptor associated death domain Receptor; EC, Endothelial cells; SMC, Smooth muscle cells; NFKB, Nuclear factor for kappa B; NIK, NFKB inducing kinase; IKK, Inhibitor of 1 kappaB kinase; JNK, c-Jun N-terminal kinase; Bid, BH3 interacting domain.