Prevention of atherosclerotic plaque destabilization

Ondertitel:focus on necroptosis, pyroptosis and ferroptosis

The stability of an atherosclerotic plaque determines its fate, either toward a low-risk lesion with a thick fibrous cap, or toward a high-risk lesion with an inflammatory necrotic core and a thin fibrous cap prone to rupture. Because a large necrotic core, induced by necrosis, is a prominent feature of advanced plaques with a major impact on atherogenesis and plaque destabilization, pharmacological modulation of necrosis represents a promising therapeutic approach to prevent plaque destabilization. Markers of regulated necrosis pathways, in particular necroptosis, pyroptosis and ferroptosis are present in advanced atherosclerotic plaques. Therefore, we targeted necroptosis, pyroptosis and ferroptosis in atherosclerosis and evaluated their potential as plaque stabilizing strategies. To limit intraplaque necroptosis, we targeted RIPK1 (receptor-interacting serine/threonine protein kinase 1) enzymatic activity using a genetic and a pharmacological approach. First, we repressed RIPK1 kinase activity using a RIPK1S25D/S25D mutation in atherosclerotic ApoE-/- mice. Interestingly, ApoE-/- RIPK1S25D/S25D mice developed larger plaques with increased deposition of extracellular matrix components. Next, we administered the pharmacological RIPK1 kinase inhibitor GSK’547 in ApoE-/- Fbn1C1039G+/- mice, a model of advanced atherosclerosis. Importantly, GSK’547 did not affect plaque size and necrosis but increased apoptosis. Thus, clearly targeting RIPK1 kinase activity is not an ideal approach to limit plaque progression and necrosis. Gasdermin D (GSDMD) is the executor-protein of pyroptosis and we were the first to report its expression in human plaques. Next, we targeted GSDMD in atherosclerosis using ApoE-/- Gsdmd-/- mice. While stable plaque formation in the aorta was not altered, ApoE-/- Gsdmd-/- mice developed smaller plaques with smaller necrotic cores and a less inflammatory plaque phenotype in the brachiocephalic artery. Therefore, inhibiting GSDMD appears as a promising plaque stabilizing approach. Intraplaque (IP) hemorrhage contributes significantly to plaque instability, but exact mechanisms are not clear-cut. We showed that phagocytosis of free erythrocytes by macrophages (erythrophagocytosis) induces ferroptosis and that markers of erythrophagocytosis-induced ferroptosis are expressed in advanced plaques. The ferroptosis inhibitor UAMC-3203 blocked erythrophagocytosis-induced ferroptosis in vitro and limited plaque progression in ApoE-/- Fbn1C1039G+/- mice with more advanced stages of atherosclerosis, especially in plaques with confirmed IP hemorrhage, but not in earlier stages of the disease or in hemorrhage-free plaques. Thus, erythrophagocytosis-induced ferroptosis provides a link between IP hemorrhage and plaque destabilization, and can be efficiently blocked with UAMC-3203. In conclusion, targeting RIPK1 kinase activity did not limit plaque necrosis and progression while inhibition of pyroptosis and ferroptosis are promising strategies to prevent plaque destabilization.

Jaar van publicatie:2022

Trefwoorden:Doctoral thesis

Toegankelijkheid:Closed