Stabilization of atherosclerotic plaques via inhibition of regulated necrosis.

Morphological studies indicate that the vast majority of dying cells in advanced human atherosclerotic plaques undergo necrosis. Although the role of necrosis in atherosclerosis remains ill-defined, a growing body of evidence suggests that necrotic death stimulates atherogenesis and plaque instability through induction of inflammation and enlargement of a central necrotic core. For a long time, necrosis has been considered as a merely accidental and uncontrolled form of cell death, but recent data suggest that it can also occur in a regulated fashion. Necroptosis is the best characterized form of regulated necrosis and requires receptor interacting protein kinases (RIPKs) as key regulators. However, other examples such as ferroptosis are also emerging. Because regulated necrosis is considered as an important research target to stabilize plaques, the following objectives are defined: (1) inhibition of necroptosis and ferroptosis in atherosclerosis using mice containing catalytically inactive RIPK1, or transgenic mice overexpressing the anti-ferroptosis enzyme GPX4, (2) stabilization of atherosclerotic plaques with potent and selective inhibitors targeting necroptosis or ferroptosis, and (3) identification of the molecular mechanisms modulating regulated necrosis in atherosclerosis. This project may lead to the discovery of novel anti atherosclerosis therapies, and will allow a significant advance in the fundamental understanding of regulated necrosis in atherosclerosis.

Keywords:NECROPTOSIS, FERROPTOSIS, ATHEROSCLEROSIS

Disciplines:Pharmacology not elsewhere classified, Vascular diseases