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Impact of myeloid RIPK1 gene deletion on atherogenesis in ApoE-deficient mice. 2021

Isabelle Coornaert, and Pauline Puylaert, and Giullia Marcasolli, and Mandy O J Grootaert, and Peter Vandenabeele, and Guido R Y De Meyer, and Wim Martinet
Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.

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. We aimed to investigate the impact of myeloid-specific RIPK1 gene deletion on atherogenesis. RIPK1F/FLysM-Cre+ApoE-/- and RIPK1+/+LysM-Cre+ApoE-/- mice were fed a western-type diet (WD) for 16 or 24 weeks to induce plaque formation. After 16 weeks WD, plaque area and percentage necrosis in RIPK1F/FLysM-Cre+ApoE-/- mice were significantly decreased as compared to plaques of RIPK1+/+LysM-Cre+ApoE-/- mice. Moreover, plaques of RIPK1F/FLysM-Cre+ApoE-/- mice showed more apoptosis and a decreased macrophage content. After 24 weeks WD, plaque size and percentage necrosis were no longer different between the two groups. Free apoptotic cells strongly accumulated in plaques of RIPK1F/FLysM-Cre+ApoE-/- mice. In addition to apoptosis, necroptosis was upregulated in plaques of RIPK1F/FLysM-Cre+ApoE-/- mice. In vitro, TNF-α triggered apoptosis in RIPK1F/FLysM-Cre+ApoE-/-, but not in RIPK1+/+LysM-Cre+ApoE-/- macrophages. Moreover, RIPK1F/FLysM-Cre+ApoE-/- macrophages were not protected against RIPK3-dependent necroptosis. The impact of myeloid RIPK1 gene deletion depends on the stage of atherogenesis. At 16 weeks WD, myeloid RIPK1 gene deletion resulted in increased apoptosis, thereby slowing down plaque progression. However, despite decreased macrophage content, plaque and necrotic core size were no longer reduced after 24 weeks of WD, most likely due to the accumulation of free apoptotic and necroptotic cells.

UI MeSH Term Description Entries
D009336 Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply.
D000074085 Mice, Knockout, ApoE Strains of mice that contain genetic disruptions (knockout) of APOLIPOPROTEINS E genes. They are used as models for ATHEROSCLEROSIS research. Apo E Knockout Mice,ApoE Knockout Mice,Knockout Mice, ApoE,Mice, ApoE Knockout
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D017353 Gene Deletion A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. Deletion, Gene,Deletions, Gene,Gene Deletions
D050197 Atherosclerosis A thickening and loss of elasticity of the walls of ARTERIES that occurs with formation of ATHEROSCLEROTIC PLAQUES within the ARTERIAL INTIMA. Atherogenesis,Atherogeneses,Atheroscleroses
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D053422 Receptor-Interacting Protein Serine-Threonine Kinases A family of serine-threonine kinases that plays a role in intracellular signal transduction by interacting with a variety of signaling adaptor proteins such as CRADD SIGNALING ADAPTOR PROTEIN; TNF RECEPTOR-ASSOCIATED FACTOR 2; and TNF RECEPTOR-ASSOCIATED DEATH DOMAIN PROTEIN. Although they were initially described as death domain-binding adaptor proteins, members of this family may contain other protein-binding domains such as those involving caspase activation and recruitment. RIP Serine-Threonine Kinases,RIP (Receptor Interacting Protein),RIP Serine-Threonine Kinase,Receptor Interacting Protein RIP,Receptor-Interacting Protein Serine-Threonine Kinase 1,Receptor-Interacting Protein Serine-Threonine Kinase 3,Kinase, RIP Serine-Threonine,Kinases, RIP Serine-Threonine,RIP Serine Threonine Kinase,RIP Serine Threonine Kinases,Receptor Interacting Protein Serine Threonine Kinase 1,Receptor Interacting Protein Serine Threonine Kinase 3,Receptor Interacting Protein Serine Threonine Kinases,Serine-Threonine Kinase, RIP,Serine-Threonine Kinases, RIP

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