Spermidine reduces lipid accumulation and necrotic core formation in atherosclerotic plaques via induction of autophagy

Background and aims: Spermidine is an endogenous biological polyamine that exhibits broad longevity extending activities via the induction of autophagy. Because basal autophagy is atheroprotective during early atherosclerosis but dysfunctional in advanced plaques, the aim of the present study was to assess the potential beneficial effects of autophagy induction by spermidine on atherosclerotic plaque progression and composition. Methods: Apolipoprotein E-deficient (ApoE(-/-)) mice were fed a Western-type diet for 20 weeks with or without 5 mM spermidine in the drinking water. Results: (Immuno-)histochemical analysis of plaques in the aortic root, proximal ascending aorta and brachiocephalic artery showed that spermidine changed neither the size of the plaque nor its cellular composition. However, spermidine treatment significantly reduced necrotic core formation (6.6 +/- 0.5% vs. 3.7 +/- 0.5% in aortic root, p = 0.0008) and lipid accumulation inside the plaque (27 +/- 3% vs. 17 +/- 1% oil red O positivity in thoracic aorta, p = 0.017). In vitro experiments showed that macrophages, unlike vascular smooth muscle cells (VSMCs), were relatively insensitive to autophagy induction by spermidine. Along these lines, spermidine triggered cholesterol efflux in autophagy-competent VSMCs (5.7 +/- 1.2% vs. 8.7 +/- 0.2%, p = 0.0118), but not in autophagy-deficient Atg7(F/F) SM22 alpha-Cre(+) VSMCs or macrophages. Analogous to the experiments in vitro, spermidine affected neither necrosis nor lipid load in plaques of Atg7(F/F) SM22 alpha-Cre(+) ApoE(-/-) mice. Conclusions: Spermidine inhibits lipid accumulation and necrotic core formation through stimulation of cholesterol efflux, albeit without changing plaque size or cellular composition. These effects, which are driven by autophagy in VSMCs, support the general idea that autophagy induction is potentially useful to prevent vascular disease. (C) 2016 Elsevier Ireland Ltd. All rights reserved.