Low‐dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking the LDL receptor

Abstract

Background and purpose:Chronic proliferative responses of different vascular cell types have been involved in the pathogenesis of atherosclerosis. However, their functional role remains to be established. Sirolimus reduces neointimal proliferation after balloon angioplasty and chronic graft vessel disease. These studies were undertaken to investigate the effects of this anti-proliferative drug on atherogenesis. Experimental approach: Low-density lipoprotein receptor-deficient (LDL r-KO) mice on a cholesterol-rich diet were randomized to receive placebo or sirolimus (0.1; 0.3; or 1 mg·kg -1 ) in their diet for 8 or 16 weeks. Results: In both studies, plasma levels of the drug increased in a dose-dependent fashion, animals gained weight normally and, among groups, plasma lipids levels did not differ significantly. Compared with placebo, plasma levels of interleukin-6, monocyte chemoattractant protein-1, interferon g, tumour necrosis factor a and CD40, and their mRNA levels in aortic tissue were significantly reduced in sirolimus-treated mice. This effect resulted in a significant and dose-dependent reduction in atherosclerotic lesions, in both the root and aortic tree. Also these lesions contained less monocyte/macrophages and smooth muscle cells, but more collagen. Conclusions and implications:The present results demonstrated that at low doses, sirolimus was an effective and safe anti-atherogenic agent in the LDL r-KO mice. It attenuated the progression of atherosclerosis and modulated the plaque phenotype by reducing the pro-inflammatory vascular responses typical of the disease.

Autophagy Links Inflammasomes to Atherosclerotic Progression

“…No studies have addressed this notion directly. However, sirolimus and everolimus, both inhibitors of the autophagy-suppressing kinase mTOR and thus classic stimulators of autophagy, are anti-atherogenic in mice (Castro et al, 2004; Mueller et al, 2008; Pakala et al, 2005; Zhao et al, 2009). Calorie-restricted mice, another stimulus for autophagy induction (Wohlgemuth et al, 2007), also have reduced atherosclerosis (Guo et al, 2002).…”

Autophagy in Vascular Disease

“…by guest on May 9, 2018 http://circres.ahajournals.org/ Downloaded from to decreased LDLR expression. Rapamycin/rapalogs downregulate hepatic LDLR expression in mice via mTORC1, leading to elevated LDL-cholesterol levels.…”

“…Administration of rapalogs in mouse or rabbit models of atherosclerosis, either orally or subcutaneously, results in a marked reduction of both plaque size and plaque complexity despite severe hypercholesterolemia. [96][97][98][99][100][101][102][103][104][105] Indeed, rapalogs can prevent accumulation of macrophages and lipids and reduce cell proliferation and intraplaque angiogenesis via mTOR inhibition. 48 However, it is currently not known whether autophagy is involved in these plaque-stabilizing effects.…”

Lower CSF Amyloid Beta Peptides and Higher F2-Isoprostanes in Cognitively Intact Elderly Individuals With Major Depressive Disorder

“…In some studies, CSF isoprostane levels, considered to be a biomarker of oxidative stress (30), which is characteristic of inflammation (31), have been associated with CSF levels of amyloid beta 42 (32). Both oxidative stress and inflammatory mechanisms have also been implicated in depression, and higher plasma isoprostane levels have been observed in elderly depressed patients relative to healthy comparison subjects (33).…”