Everolimus depletes plaque macrophages, abolishes intraplaque neovascularization and improves survival in mice with advanced atherosclerosis

Abstract

Background and aims: Inhibition of the mechanistic target of rapamycin (mTOR) is a promising approach to halt atherogenesis in different animal models. This study evaluated whether the mTOR inhibitor everolimus can stabilize pre-existing plaques, prevent cardiovascular complications and improve survival in a mouse model of advanced atherosclerosis. Methods: ApoE-/-Fbn1 C1039G+/mice (n=24) were fed a Western diet (WD) for 12 weeks. Subsequently, mice were treated with everolimus (1.5 mg/kg daily) or vehicle for another 12 weeks while the WD continued. Results: Despite hypercholesterolemia, everolimus treatment was associated with a reduction in circulating Ly6C high monocytes (15 vs. 28% of total leukocytes, p=0.046), a depletion of plaque macrophages (2.1 vs. 4.1%, p=0.040) and an abolishment of intraplaque neovascularization, which are all indicative of a more stable plaque phenotype. Moreover, everolimus reduced hypoxic brain damage and improved cardiac function, which led to increased survival (100 vs. 67% of animals, p=0.038). Conclusions: Everolimus enhances features of plaque stability and counters cardiovascular complications in ApoE-/-Fbn1 C1039G+/mice, even when administered at a later stage of the disease.

Chronic everolimus treatment of high‐fat diet mice leads to a reduction in obesity but impaired glucose tolerance

“…The HFD control group were administered the corresponding volume of the vehicle (8% ethanol, 10% PEG 400, and 10% Tween 80) 24 . The everolimus dose was selected according to the literature regarding the use of everolimus as a candidate for chronic treatment in metastatic breast cancer, atherosclerosis, xenograft, heart transplantation, hypercholesterolemia, and endometriotic studies in a mouse model 25–30 …”

“…24 The everolimus dose was selected according to the literature regarding the use of everolimus as a candidate for chronic treatment in metastatic breast cancer, atherosclerosis, xenograft, heart transplantation, hypercholesterolemia, and endometriotic studies in a mouse model. [25][26][27][28][29][30] 2.2 | Body weight, tissue and organ weight, food intake, as well as serum hormone, fatty acid, fibroblast growth factor 21, interleukin 1β, and tumor necrosis factor α level measurement Every week, we measured the mice's body weights. In addition, we measured the food intake weekly by weighing the food left in each cage including that in each cage's dispenser and floor.…”

The tandem stenosis mouse model: Towards understanding, imaging, and preventing atherosclerotic plaque instability and rupture

“…Importantly, this model recreates several clinical consequences of atherosclerosis, including MI, stroke, and a high incidence of spontaneous death (70% by 35 weeks). Similarly to the TS model, this approach has now been used to interrogate biological mechanisms, as well as test diagnostic and therapeutic approaches (De Dominicis et al, 2020; De Wilde et al, 2015; Kurdi et al, 2019; Luyckx et al, 2018; Perrotta, Pintelon, et al, 2020; Perrotta, Van der Veken, et al, 2020; Roth et al, 2015, 2019; Roth, Rombouts, et al, 2016; Roth, Schrijvers, et al, 2016; Van der Donckt, Roth, et al, 2015; Van der Veken et al, 2018).…”

Phenotype and Response to PAMPs of Human Monocyte-Derived Foam Cells Obtained by Long-Term Culture in the Presence of oxLDLs

“…Furthermore, foam cells derived from THP-1 macrophages in 72 h culture did not respond to everolimus (an FDA-approved rapalog) with necrosis (74). Indeed, limited clinical data show substantial depletion of plaque macrophages by everolimus treatment (75), which may result from excessive necrosis without a corresponding production of IL-1β. Cumulatively, the data from short-term-induced foam cells demonstrated an important limitation of the model which does not fully reflect the cross-talk between different processes connected with cell death, particularly pyroptosis, necroptosis and autophagy.…”