This activation is accomplished by recruitment of caspase-8, followed selleck inhibitor by its proteolytic activation. Once activated, caspase-8 can proteolytically cleave the BH3-interacting death domain agonist (Bid), a proapoptotic member of the Bcl-2 family proteins, leading to the formation of a truncated Bid form (tBid) that, in turn, activates the mitochondrial apoptotic pathway [115�C117]. Alternatively, the activated initiator caspase-8/-10, in turn, targets the effector caspase-3 for proteolytic cleavage which, once activated, cleaves other caspases as well as numerous regulatory and structural proteins [118, 119], resulting in the appearance of the hallmarks of apoptosis such as membrane blebbing, internucleosomal DNA fragmentation, and nuclear shrinkage [120].

TRAIL firstly received considerable attention as a molecule showing the ability to induce apoptosis in a wide variety of neoplastic cells [121]. However, many normal cells, such as thymocytes [121], neural cells [122], hepatocytes [123], osteoclasts [124�C126], osteoblasts [127�C129], VSMCs [130], and VICs [8], are sensitive to TRAIL-induced apoptosis.TRAIL in CAVD. VICs sensitivity to TRAIL apoptotic effect is of paramount importance because apoptosis has been shown to be an initiator of vascular calcification in in vitro studies [131]; increased apoptosis precedes calcification in VSMC cultures, and apoptotic bodies may act as nucleating structures for calcium crystal formation [131]. Previous studies focused on the role of apoptosis in the pathogenesis of CAVD [7, 132, 133].

TGF-��1 is present in human calcific aortic stenotic cusps and promotes calcification of cultured sheep aortic VICs (SAVICs) through mechanisms involving apoptosis [7]; in fact, the administration of an apoptosis inhibitor to SAVICs cultured in an osteogenic environment results in a significant Dacomitinib decrease in nodules calcification, thereby demonstrating that a certain level of apoptosis is necessary for the calcification of nodules in these cultures [7]. TRAIL has been detected in atherosclerotic lesions [134], and TRAIL-expressing T-cells induce apoptosis of VSMCs in the atherosclerotic plaque [130]. TRAIL is expressed in human calcified aortic valves but not in normal ones, and it is mainly produced by T-cell and macrophages. Moreover, serum levels of TRAIL are significantly elevated in patients with CAVD compared to normal subjects [8]. VICs derived from calcific and noncalcific aortic valves express both death and decoy TRAIL receptors; in particular, VICs derived from calcific valves show significantly higher gene and protein levels of DR4, DR5, DcR1, and DcR2 compared to VICs derived from noncalcific valves [8].