GPX4 overexpression does not alter atherosclerotic plaque development in ApoE knock-out mice.

Ferroptosis is a type of regulated necrosis that is associated with iron-dependent accumulation of lipid hydroperoxides. Given that iron deposition and lipid peroxidation initiate ferroptosis in atherosclerosis and contribute to further plaque development, we hypothesized that inhibition of ferroptosis could be of value in the treatment of atherosclerosis. Glutathione peroxidase 4 (GPX4) is the only enzyme known capable of reducing lipid hydroperoxides.

α-Tocopherol inhibits atherogenesis and improves cardiac function in mice independently of its antioxidant properties.

The impact of α-tocopherol on atherosclerosis is unclear and controversial. While some studies suggest potential benefits, such as antioxidant properties that may reduce oxidative stress, other studies indicate no significant preventive effects. The intricate interplay of various factors, including dosage, individual differences, and study methodologies, contributes to the ongoing uncertainty surrounding α-tocopherol's role in atherosclerosis.

The Impact of RIPK1 Kinase Inhibition on Atherogenesis: A Genetic and a Pharmacological Approach.

RIPK1 (receptor-interacting serine/threonine-protein kinase 1) enzymatic activity drives both apoptosis and necroptosis, a regulated form of necrosis. Because necroptosis is involved in necrotic core development in atherosclerotic plaques, we investigated the effects of a RIPK1 mutation, which prevents activation of RIPK1 kinase, on atherogenesis in ApoE mice. After 16 weeks of western-type diet (WD), atherosclerotic plaques from ApoE RIPK1 mice were significantly larger compared to ApoE RIPK1 mice (167 ± 34 vs.

GSK-7975A, an inhibitor of Ca release-activated calcium channels, depresses isometric contraction of mouse aorta.

GSK-7975A is described to inhibit stromal interaction molecule 1(STIM1)-mediated Ca release-activated Ca channels ORAI 1, ORAI 2 and ORAI 3 in different cell types. The present study investigated whether isometric contractions of mouse aortic segments were affected by this selective store-operated calcium channel inhibitor. Depending on the way by which Ca influx pathways were activated during contraction, GSK-7975A inhibited contractility of mouse aortic segments with different affinity.

Impact of myeloid RIPK1 gene deletion on atherogenesis in ApoE-deficient mice.

Background And Aims: Targeting macrophage death is a promising strategy for stabilizing atherosclerotic plaques. Recently, necroptosis was identified as a form of regulated necrosis in atherosclerosis. Receptor-interacting serine/threonine-protein kinase (RIPK)1 is an upstream regulator of RIPK3, which is a crucial kinase for necroptosis induction.

Macrophage Death as a Pharmacological Target in Atherosclerosis.

Atherosclerosis is a chronic inflammatory disorder characterized by the gradual build-up of plaques within the vessel wall of middle-sized and large arteries. Over the past decades, treatment of atherosclerosis mainly focused on lowering lipid levels, which can be accomplished by the use of statins. However, some patients do not respond sufficiently to statin therapy and therefore still have a residual cardiovascular risk.

Novel drug discovery strategies for atherosclerosis that target necrosis and necroptosis.

Formation and enlargement of a necrotic core play a pivotal role in atherogenesis. Since the discovery of necroptosis, which is a regulated form of necrosis, prevention of necrotic cell death has become an attractive therapeutic goal to reduce plaque formation. Areas covered: This review highlights the triggers and consequences of (unregulated) necrosis and necroptosis in atherosclerosis.