Role of autophagy in the normal and atherosclerotic vessel wall

Date: 8 November 2016

Venue: UAntwerpen, Campus Drie Eiken - Building Q - promotiezaal - Universiteitsplein 1 - 2610 Antwerp (Wilrijk) (route: UAntwerpen, Campus Drie Eiken)

Time: 4:30 PM - 6:30 PM

PhD candidate: Cédéric Michiels

Principal investigator: Guido De Meyer

Co-principal investigator: Wim Martinet

Short description: PhD Cédéric Michiels - Department of Pharmaceutical Sciences


Cardiovascular disease (CVD) is still the main underlying cause of death worldwide. Because current therapies do not suffice in preventing the manifestation of CVD, there is a profound interest to identify novel mechanisms that govern cardiovascular homeostasis. Autophagy, an evolutionary preserved process that prevents the accumulation of unwanted cytosolic material through autophagosome formation, has been shown to have pronounced activity in the circulatory system. However, the role of autophagy in vascular smooth muscle cells (VSMC), more specifically in Ca2+ mobilization and contraction, remains poorly understood. Our research demonstrated that voltage-gated Ca2+ channels of mice with a VSMC-specific autophagy defect (Atg7F/FSM22α-Cre+) were more active and also more sensitive to depolarization. Moreover, we could show that the sarcoplasmic reticulum of Atg7F/FSM22α-Cre+ VSMCs was enlarged, which in combination with increased SERCA2 expression and higher store-operated Ca2+ entry, promoted inositol 1,4,5-trisphosphate-mediated contractions. These results indicate that defective autophagy in VSMCs influences Ca2+ homeostasis and significantly affects vascular reactivity.

Interestingly, transmission electron microscopy revealed that autophagy also occurs in atherosclerosis. Autophagy is triggered during early atherosclerosis to protect vascular cells from cell death, whereas it is compromised in advanced lesions and linked with increased plaque development. In the literature, a general consensus exists that autophagy induction might serve as a promising strategy in the prevention/treatment of atherosclerosis. Therefore, we assessed the potential beneficial effects of the autophagy inducer spermidine on atherosclerotic plaques in mice lacking the ApoE­-gene. Histochemical analysis showed that spermidine significantly reduced necrotic core formation and lipid accumulation inside the plaque. Furthermore, spermidine stimulated autophagy and triggered cholesterol efflux in autophagy-competent Atg7+/+SM22α-Cre+ VSMCs, but not in autophagy-deficient Atg7F/FSM22α-Cre+ VSMCs or macrophages. Analogous to previous findings, spermidine affected neither necrosis nor lipid load in plaques of Atg7F/FSM22α-Cre+xApoE-/- mice. Next, we performed the same set of experiments with metformin. Apart from its glucose-lowering properties, metformin also reduces the development of micro- and macrovascular complications, such as atherosclerosis, in diabetic patients. Metformin has been extensively described as a potent autophagy inducer through mTOR inhibition via AMPK. Our data demonstrated that metformin delayed atherosclerotic plaque development in the brachiocephalic artery, with plaques showing a reduced number of macrophages, an increased amount of VSMCs and a higher collagen content. In vitro experiments with HUVECs further revealed that metformin reduced VCAM-1/ICAM-1 expression and prevented monocyte adhesion via induction of autophagy. These findings indicate that metformin slows down atherogenesis and leads to a more stable plaque phenotype in an autophagy-dependent manner.

In general, we provide crucial evidence that autophagy is indispensable for maintaining homeostasis in the vascular system, more specifically in controlling vascular function and limiting atherosclerosis.