TRAIL: A novel atheroprotective mechanism in the vasculature

Abstract

The vasculature is critical for the maintenance of cardiovascular homeostasis. Cardiovascular disease (CVD) is characterised by endothelial cell (EC) and vascular smooth muscle cell (VSMC) dysfunction, in which vascular oxidative stress is a primary cause. The mechanisms and stimuli involved in vascular dysfunction are not fully characterised. Our lab showed that TNF-related apoptosis-inducing ligand (TRAIL) is a master regulator of vascular cell function, and its deletion in Apoe-/- mice accelerated atherosclerosis and CVD. TRAIL is increasingly recognised to play a protective role in CVD, however, how it may regulate vascular function is unclear. This thesis aimed to investigate TRAIL’s protective role against oxidative stress resulting in CVDs. It studied TRAIL’s role in clinical, pre-clinical and in-vitro models. This thesis also aimed to elucidate the mechanism of action of TRAIL in vascular cells in vivo using cell-specific TRAIL knockout mouse models under normal and pathological conditions. This thesis demonstrated that: i. Circulating plasma TRAIL and oxidative stress markers are negatively correlated in patients with coronary artery disease (CAD). ii. Following high fat diet (HFD), mice lacking TRAIL had endothelial dysfunction, vascular inflammation and increased vessel permeability. iii. TRAIL protected against angiotensin II (AngII)-induced oxidative stress in vitro in ECs. TRAIL also negated AngII-induced cell processes by reducing monocyte adhesion and improving permeability in-vitro in ECs. iv. EC-specific TRAIL deleted mice challenged with an HFD, experienced high plasma cholesterol, reduced blood pressure and altered gene expression profiles for inflammatory markers compared to wild type mice. v. VSMC-specific TRAIL deleted mice challenged with an HFD, displayed altered expression of genes regulating VSMC phenotype. These mice also had an enlarged liver compared to wild type mice in response to an HFD. This thesis provided novel insight into the protective role of TRAIL against endothelial dysfunction via its ability to modulate oxidative stress. This thesis studied the mechanism of action of TRAIL in vascular cells. Thus, understanding the role TRAIL plays in normal physiology and disease, may lead to potential new therapies to improve vascular functions and CVDs.