Molecular Indices of Apoptosis Activation in Elastase-Induced Aneurysms After Embolization With Platinum Coils

Abstract

Background and Purpose-Even though endovascular coils have been widely used for the treatment of intracranial aneurysms, the cellular and molecular responses of aneurysms to the coils after embolization remain poorly understood. The aim of the present study was to understand the mechanism of apoptosis in aneurysms embolized with platinum coils in the rabbit model of elastase-induced aneurysms. Methods-Elastase-induced saccular aneurysms were created at the origin of the right common carotid artery in 30 rabbits.Aneurysms were allowed to mature for 8 weeks, after which 20 aneurysms were embolized with platinum coils by endovascular means. After 2 (nϭ10) and 4 (nϭ10) weeks of implantation, aneurysm samples harboring coils were harvested for apoptotic studies. The remaining 10 uncoiled aneurysms were used as controls; additional controls included the left common carotid artery, which had not undergone any surgical procedure. Control samples were harvested at 12 weeks after aneurysm creation. Results-Expression of procaspases-3, -8, and -9 was elevated in coiled aneurysms embolized with platinum coils at both time points when compared with uncoiled aneurysms and the left common carotid artery. Cleaved caspases-3, -8, and -9 were found to be expressed only at 4 weeks after embolization. Cells within the aneurysm cavity were terminal dUTP nick end-labeling-positive at 4 weeks only. These apoptotic cells were identified as smooth muscle actin-positive cells. Expression of tumor necrosis-␣ was high in coiled aneurysms when compared with controls. There was no significant difference in the expression of Fas ligand among groups. Decreased expression of antiapoptotic proteins Bcl-2 and phospho-Bad, as well as increased expression of proapoptotic proteins Bax and Bid, was observed in coiled aneurysms at both time points. Conclusions-Activation of apoptosis in aneurysms after embolization with platinum coils is induced by both tumor necrosis factor-␣-mediated extrinsic and Bcl-2-mediated intrinsic pathways.

Genomics of Human Intracranial Aneurysm Wall

“…16 Moreover, both TNF-␣-mediated extrinsic and Bcl-2-mediated intrinsic apoptotic pathways induced apoptosis in a rabbit aneurysm model. 28 These data, therefore, indicate that genes involved in both intrinsic and extrinsic apoptotic pathways may contribute to the pathogenesis of IAs.…”

Bone Morphogenetic Protein-7 Ameliorates Cerebral Ischemia and Reperfusion Injury via Inhibiting Oxidative Stress and Neuronal Apoptosis

“…Caspase-9 is a crucial up-stream initiator enzyme in the mitochondria-mediated apoptotic pathway and its activation can be achieved either by cleavage or by association with apoptotic protease activating factor 1 (Apaf-1) to form the active apoptosome [36]. In the death receptor pathway, ligation of a receptor belonging to the tumor necrosis factor (TNF) receptor family leads to the induction of apoptosis through activation of caspase-8 [37]. Both activated caspase-9 and activated caspase-8 can further catalyze down-stream caspases including the major effector enzyme caspase-3, which leads to DNA fragmentation and subsequently to apoptotic cell death.…”

Mechanisms of Healing in Coiled Intracranial Aneurysms: A Review of the Literature

“…Histologic studies of rabbit aneurysms have demonstrated that there is increased expression of activated cleaved caspases at four weeks following coil embolization 27 . Apoptosis of myofibroblasts in the aneurysm dome has been shown to be mediated by both intrinsic (Bcl-2/mitochondrial mediated) and extrinsic (TNF-alpha/receptor mediated) pathways of apoptosis 30 .…”