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Atherosclerosis regulation via media lipid-driven VSMC cholesterol efflux switch.

Significance Statement

 

It was proposed atherosclerosis regulation mechanism via media VSMC activation ahead of macrophage and endothelial cell responses. This mechanism may be an universal. It contradicts much of generally accepted disease onset hypotheses. Author assumes that molecular events of each proposed hypothesis are not diverse, and belong to post-effects of signals, which account for separate cell involvement in intima, selectively participating in lipoprotein metabolism and inflammatory response. Irrespective of cause disease it evokes a new additional players at intermediate stages of various lipoprotein class trafficking, sorting and their reutilization via an obligatory VSMC switches after selective receptor involvement in compartments with secondary messengers to nucleus. Each of them have a dual function (or more), promoting lipoprotein (cholesterol) efflux regulation, and at the same time, regulating non –, and inflammatory phases of atherosclerosis by prohibiting and activating signals. Apart from, these messengers may not or be inserted into the activation of ABCA-1 and ABCG-1-responsive genes, behave independently off them, supporting low macrophage and other intima cell response even in cases of early and/or late non effective efflux. As it was proposed, each messengers may act by unusual manner for VSMC, becoming , via promoters and activators of various genes. They may appear through different mechanisms everywhere – from membranes, in cytoplasm, departments, within nucleus. It is known nothing on interaction of lipoprotein efflux-responsive genes and involved in VSMC proliferation. It is proposed that oxidized LDL may activate  simultaneously or separately Vnt/β-catenin signaling pathway with NF-kB involvement via enhancer or promoters of two neighbouring specific sequences of DNA,  regulating VSMC proliferation levels in media/intima, and lipoprotein uptake and removal. Initial phases of cholesterol, mmLDL, and ROS-product, another lipoprotein effluxes from a proliferative media VSMC arises via NF-kB/LXR activation.  Some waves of NF-kB activity are needed  for normal and regulated of anti-atherosclerosis lipoprotein metabolism levels. The next activation may be evoked after intimal VSMC overload by oxLDL via intranuclear switch to PPAR with weak inflammatory signals for attraction of some new intima cells, EC activation. NF-kB/PPAR switch cooperation are principal for resolution of inflammation via their feed-back influences or via low intermittent inflammatory signals for intima cell activation. Regulation of corresponding genes allows to decrease media/intima and VSMC lipid burden for restoration of lipoprotein removal. Apart from, self-regulatory mechanism by low signals (via tandem LXR/PPAR) during long period of atherosclerosis may be disturbed via of LXR/PPAR/SREBP with intermittent or constant strong inflammatory signals to intima. Finally, the atherosclerosis  regulation model via VSMC activation and its testing could be useful to screen intermediate molecules and executors at cytoplasm and transcriptional  levels and will provide key targets of early and late molecular events for therapy strategy.

 

Journal Reference

Chepelenko GV. Med Hypotheses. 2015 ;84(2):141-4.

N.A. Semashko Central Clinical Hospital, Moscow, Russia. Electronic address: [email protected]

Abstract

It is known, that initial events in atherosclerosis arise in the intima with a parallel influx of inflammatory cells. I propose the opposite – that the disease onset begins from the media vascular smooth muscle cell (VSMC) involvement and through its utilization of modified low-density lipoproteins (LDL), and free or esterified cholesterol. Other oxidized lipoprotein molecules remain in the media which are non-removed by high-density lipoproteins (HDL), owing to their structural damages after local vasa vasorum and adventitia lymphatic disorders. Mechanism by which VSMC ingulf and degrade them includes lipid-driven activation of VSMC reverse cholesterol transport pathways from the media to macrophages, and from the last – to plasma HDL (non-damaged) and apoA-1 or – directly to them. When some of the pathways are impaired, its demands a reprogramming of the existing cholesterol removal route to another, or selective gene involvements and transcriptional regulation of inflammatory signaling. Intima cell call-effects may be linked after their down-regulation with the expression of cytokines, chemokines by migrating VSMC to stem cells for dose-dependent proliferation, VSMC and macrophage maturation in non- and inflammatory phases of early or late atherosclerosis.

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