Molecular Etiology of Atherogenesis – In Vitro Induction of Lipidosis in Macrophages with a New LDL Model

Abstract

BackgroundAtherosclerosis starts by lipid accumulation in the arterial intima and progresses into a chronic vascular inflammatory disease. A major atherogenic process is the formation of lipid-loaded macrophages in which a breakdown of the endolysomal pathway results in irreversible accumulation of cargo in the late endocytic compartments with a phenotype similar to several forms of lipidosis. Macrophages exposed to oxidized LDL exihibit this phenomenon in vitro and manifest an impaired degradation of internalized lipids and enhanced inflammatory stimulation. Identification of the specific chemical component(s) causing this phenotype has been elusive because of the chemical complexity of oxidized LDL.Methodology/Principal FindingsLipid “core aldehydes" are formed in oxidized LDL and exist in atherosclerotic plaques. These aldehydes are slowly oxidized in situ and (much faster) by intracellular aldehyde oxidizing systems to cholesteryl hemiesters. We show that a single cholesteryl hemiester incorporated into native, non-oxidized LDL induces a lipidosis phenotype with subsequent cell death in macrophages. Internalization of the cholesteryl hemiester via the native LDL vehicle induced lipid accumulation in a time- and concentration-dependent manner in “frozen" endolysosomes. Quantitative shotgun lipidomics analysis showed that internalized lipid in cholesteryl hemiester-intoxicated cells remained largely unprocessed in those lipid-rich organelles.Conclusions/SignificanceThe principle elucidated with the present cholesteryl hemiester-containing native-LDL model, extended to other molecular components of oxidized LDL, will help in defining the molecular etiology and etiological hierarchy of atherogenic agents.

The efficacy and mechanism of apoptosis induction by hypericin-mediated sonodynamic therapy in THP-1 macrophages

“…33 Moreover, macrophages play a crucial role in the progression and instability of atherosclerotic plaques. [34][35][36] Thus, promoting the clearance of macrophages from plaques is an alternative strategy for treating AS. SDT, which combines low-intensity ultrasound with different sonosensitizers, has been demonstrated to induce apoptosis in a variety of cell types relevant to different diseases.…”

“…Furthermore, the release of metalloproteinase from macrophages could weaken the fibrous cap of the plaque and promote rupture. 35 Therefore, the antiapoptosis effects of macrophages in early-stage atherosclerotic lesions increase the likelihood of plaque development. 34 Our group previously confirmed that PpIX could enter athermanous plaques in the rabbit carotid artery.…”

Combination of Hydroxyl Acetylated Curcumin and Ultrasound Induces Macrophage Autophagy with Anti-Apoptotic and Anti-Lipid Aggregation Effects

“…Macrophages, which accumulate in atherosclerotic plaques, play a crucial role in the occurrence of atherosclerosis [2,3]. Therefore, therapies targeting macrophages have been recognized as beneficial for plaque stability [4].…”

Relation of Oxidative Parameters of Low Density Lipoproteides With the Age in Male Population of Novosibirsk City

“…Кроме того, окЛНП оказывают влияние на развитие атеросклероза и при участии других меха-низмов. Модифицированные ЛНП ингибируют обра-зование эндотелиальными клетками фактора роста, стимулируют проникновение моноцитов в интиму, задерживают миграцию макрофагов из интимы [1,4,5]. Также окислительная модификация ЛНП зависит от их антиоксидантного потенциала.…”

“…Окислительная модификация циркулирующих в крови ЛНП менее выражена, чем в субэндотелии сосудистой стенки, где активны процессы клеточного окисления ЛНП моноцит/макрофагами, Т-лимфоци-тами и пенистыми клетками, секретирующими актив-ные кислородные метаболиты (АКМ) [4,5]. В сосудис-той стенке (интиме) часть ЛНП подвергается окисле-нию и преобразованию в модифицированные частицы.…”