Inhibition of apoptosis, autophagy and necrosis in atherosclerosis: potential strategies for plaque stabilisation?

Date: 19 September 2016

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

Time: 10:00 AM - 12:00 PM

PhD candidate: Mandy Grootaert

Principal investigator: Wim Martinet

Short description: PhD Mandy Grootaert - Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department Pharmaceutical Sciences


Atherosclerosis is a chronic, inflammatory disease characterised by the formation of atherosclerotic plaques in the arterial blood vessel wall. These plaques may narrow the lumen of the artery or completely occlude the vessel by the formation of thrombi following plaque rupture, resulting in myocardial infarction or stroke. Despite remarkable advances in cardiovascular research, atherosclerosis remains a leading cause of death in the western world. Therefore, we are searching for new strategies that prevent plaque rupture and can augment the current anti-atherosclerotic therapies. Plaque rupture is facilitated by the conversion of a stable lesion into a vulnerable, unstable plaque. One of the main mechanisms leading to plaque destabilisation is cell death of lesional macrophages and vascular smooth muscle cells (VSMCs). Therefore, we decided to investigate whether inhibition of cell death, in particular of apoptosis, autophagy, or necrosis, could have beneficial effects on the stability of atherosclerotic plaques in Apolipoprotein E deficient (ApoE-/-) mice. First, we used caspase-3 deficient mice crossbred with ApoE-/- mice as a model for apoptosis deficiency in atherosclerosis. In vitro, caspase-3 deficient macrophages and VSMCs were resistant to apoptosis, but showed increased susceptibility to necrosis. In vivo, caspase-3 deficiency promoted necrotic core formation in plaques of ApoE-/- mice. To investigate the role of autophagy in VSMCs in arterial disease, a mouse model was constructed in which the essential autophagy geneAtg7 was specifically deleted in VSMCs. Loss of Atg7 in VSMCs accelerated the development of stress-induced premature senescence.In vivo, defective VSMC autophagy promoted post-injury neointima formation and diet-induced atherogenesis which was associated with increased VSMC senescence. To test whether inhibition of necrosis would be a suitable plaque stabilising strategy, ApoE-/- mice were treated with NecroX-7, a newly developed necrosis inhibitor. NecroX-7 treatment reduced necrotic core area, oxidative stress and inflammation in plaques of ApoE-/- mice, and increased collagen deposition and fibrous cap thickness. In conclusion, inhibition of apoptosis and VSMC autophagy are unfavourable strategies to improve atherosclerotic plaque stability. In contrast, the necrosis inhibitor NecroX-7 improved several features of plaque stability in ApoE-/- mice and could therefore be a potential pleiotropic drug for the treatment of atherosclerosis.