Biology subjects

Rasheed, A.

Publications and source records attributed to Rasheed, A..

2 recordsLinked to original sources

bioRxiv2019

The Secretome of Liver X Receptor Agonist Treated Early Outgrowth Cells Decreases Atherosclerosis in Ldlr-/- Mice

ObjectiveEndothelial progenitor cells (EPCs) promote the maintenance of the endothelium by the secretion of vasoreparative factors. A population of EPCs known as early outgrowth cells (EOCs) are currently being investigated as novel cell-based therapies for the treatment of cardiovascular disease. We previously demonstrated that the absence of liver x receptors (LXRs) is detrimental to the formation and function of EOCs under hypercholesterolemic conditions. Here, we investigate whether LXR gain-of-function in EOCs is beneficial for the treatment of atherosclerosis.\n\nApproach and ResultsEOCs were differentiated from the bone marrow of wildtype (WT) and LXR-knockout (Lxr{beta}-/-) mice in the presence of vehicle or LXR agonist (GW3965). WT EOCs treated with GW3965 throughout differentiation showed reduced expression of endothelial lineage markers (Cd144, Vegfr2) compared to WT vehicle and Lxr{beta}-/- cells. GW3965-treated EOCs produced secreted factors that reduced monocyte adhesion to activated endothelial cells in culture. When injected into atherosclerosis-prone Ldlr-/- mice, GW3965-treated EOCs and concentrated conditioned media (CM) from GW3965-treated EOCs, reduced plaque burden within the aortic sinus. Furthermore, when CM from human EOCs (obtained from patients with established CAD) were treated with GW3965, monocyte to endothelial adhesion was decreased suggesting the translatability of the results.\n\nConclusionsEx vivo LXR agonist treatment of EOCs produces a secretome that decreases early atherosclerosis in Ldlr-/- mice. CM from human EOCs significantly inhibits monocyte to endothelial adhesion. Thus, active factor(s) within the GW3965-treated EOC secretome have the potential to be useful for the treatment of atherosclerosis.

cell biology↗

bioRxiv2019

Loss of MLKL Decreases Necrotic Core but Increases Macrophage Lipid Accumulation In Atherosclerosis

ObjectivesDuring the advancement of atherosclerosis, the cellularity of the plaque is governed by the influx of monocyte-derived macrophages and their turnover via apoptotic and non-apoptotic forms of cell death. Previous reports have demonstrated that programmed necrosis, or necroptosis, of macrophages within the plaque contribute to necrotic core formation. Knockdown or inhibition of the necrosome components RIPK1 and RIPK3 slow the progression of atherosclerosis, and activation of the terminal step of necroptosis, MLKL, has been demonstrated in advanced human atherosclerotic plaques. However, whether MLKL directly contributes to lesion development and necrotic core formation has not been investigated.\n\nApproaches and ResultsMLKL expression was knocked down in atherogenic Apoe- knockout mice via subcutaneous administration of antisense oligonucleotides (ASO). During advanced atherogenesis, Mlkl knockdown potently reduced cell death in the plaque, with a significant reduction in the necrotic core. However, total lesion area in the aortic sinus remained unchanged. Furthermore, treatment with the MLKL ASO unexpectedly reduced circulating cholesterol levels compared to control ASO, while staining for lipids within the plaque was significantly increased. Peritoneal macrophages transfected with the MLKL ASO showed increased lipid loading upon incubation with modified cholesterol-rich lipoproteins. In lipid-loaded macrophages, MLKL co-localized with Rab7, a marker of the late endosome.\n\nConclusionsThese studies confirm the requirement for MLKL as the executioner of necroptosis, and as such a significant contributor to the necrotic core during atherogenesis. We also identified a previously unknown role for MLKL in interacting with endosomal trafficking components to regulate lipid uptake in macrophages during atherogenesis.

pathology↗