Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

作者：Alexander Nikolaevich Orekhov, Vasily N. Sukhorukov, Nikita G. Nikiforov, Marina V. Kubekina, Igor Alexandrovich Sobenin, Kathy K. Foxx, Sergey S. Pintus, Philip Stegmaier, Daria Stelmashenko, Alexander E Kel, Anastasia Vladimirovna Poznyak, Wei‐Kai Wu, Artem S. Kasianov, Vsevolod J. Makeev, Ichiro Manabe, Yumiko Oishi · 发表于：International Journal of Molecular Sciences · 年份：2020 · DOI：10.3390/ijms21082716 · 被引用次数：42 · 研究领域：Atherosclerosis and Cardiovascular Diseases、Cholesterol and Lipid Metabolism、Lipoproteins and Cardiovascular Health

Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was show...