Inducing Autophagy as the Basis for an Atherosclerosis Treatment

More of the cellular housekeeping process of autophagy appears to be an unalloyed good: more repair means less damage. It shows up in a range of interventions that modestly slow aging in mice and other species, such as calorie restriction. In fact it may even be essential to the ability of calorie restriction to extend healthy life spans in these studies. One place in which greater levels of autophagy might do some good is in the development of atherosclerosis, a pervasive age-related condition in which an overreaction to minor molecular damage in blood vessel walls snowballs into zones of inflammation and growing plaques made up of fats and dead cells. Eventually these plaques cause ruptures or blockages of major blood vessels that are frequently fatal. Higher levels of autophagy should slow the pace of progression of this problem through increased clearance of plaque materials, though it seems clear from the data here that much more aggressive interventions to clean up the waste and damage will be needed to solve it completely. The effects are small.

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. Apolipoprotein E-deficient (ApoE-/-) mice prone to development of atherosclerosis were fed a Western-type diet for 20 weeks with or without 5 mM spermidine in the drinking water.

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) and lipid accumulation inside the plaque (27 ± 3% vs. 17 ± 1% oil red O positivity in thoracic aorta). 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%), but not in autophagy-deficient VSMCs or macrophages. Analogous to the experiments in vitro, spermidine affected neither necrosis nor lipid load in plaques of autophagy-deficient ApoE-/- mice.

In conclusion, 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.



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