Journal
SCIENTIFIC REPORTS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-022-06762-y
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Funding
- Romanian Academy
- Romanian National Authority for Scientific Research and Innovation, CCCDI-UEFISCDI project COFUND-ERA-CVD-XploreCAD, within PNCDI III
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Non-apoptotic regulated cell death and DAMPs play important roles in the progression of atherosclerotic plaques, with inadequate response to lipid-lowering treatment. Dysregulation of certain proteins involved in non-apoptotic regulated cell death and associated DAMPs may contribute to the silent evolution of atherosclerosis and possess therapeutic potential.
Non-apoptotic regulated cell death (ferroptosis and necroptosis) leads to the release of damage-associated molecular patterns (DAMPs), which initiate and perpetuate a non-infectious inflammatory response. We hypothesize that DAMPs and non-apoptotic regulated cell death are critical players of atherosclerotic plaque progression with inadequate response to lipid-lowering treatment. We aimed to uncover the silent mechanisms that govern the existing residual risk of cardiovascular-related mortality in experimental atherosclerosis. Proteomic and genomic approaches were applied on the ascending aorta of hyperlipidemic rabbits and controls with and without lipid-lowering treatment. The hyperlipidemic animals, which presented numerous heterogeneous atherosclerotic lesions, exhibited high concentrations of serum lipids and increased lipid peroxidation oxidative stress markers. The analyses revealed the significant upregulation of DAMPs and proteins implicated in ferroptosis and necroptosis by hyperlipidemia. Some of them did not respond to lipid-lowering treatment. Dysregulation of five proteins involved in non-apoptotic regulated cell death proteins (VDAC1, VDAC3, FTL, TF and PCBP1) and nine associated DAMPs (HSP90AA1, HSP90AB1, ANXA1, LGALS3, HSP90B1, S100A11, FN, CALR, H3-3A) was not corrected by the treatment. These proteins could play a key role in the atherosclerotic silent evolution and may possess an unexplored therapeutic potential. Mass spectrometry data are available via ProteomeXchange with identifier PXD026379.
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