Vascular shear forces and atherogenesis: Roles of shear-provoked endothelial viral infection and heme iron accumulation

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Abstract

This paper provides evidence for a hypothesis that shearing stresses at sites of increased vascular turbulence may foster atherogenesis in at least two separate ways. First, we have suggested that herpes viruses are activated by shear of latently infected endothelial cells. Active infection in vitro alters the vascular surface, making it adhesive for, and vulnerable to, inflammatory cells, while also altering it to become highly procoagulant. The second phenomenon accrues from red blood cell fragmentation, which we believe occurs at vascular-turbulence areas or in intramural hemorrhages within vessel walls. The resulting uptake by endothelium of released heme groups sensitizes these cells to damage by oxidants; this occurs after the heme ring is cleaved by induced endothelial heme oxygenase with release of iron. An additional deleterious effect of released heme at these sites results from its ability to potently catalyze LDL oxidation-a process remarkably and rapidly inhibited by oral supplementation with vitamin E. We have shown that heme-protein's deleterious affects on vascular wall integrity can be counteracted by the plasma constituents, haptoglobin and hemopexin. However, we suggest these factors may not be present in sufficient quantity in 'sanctuary' sites of vessel walls, such as in intramural hemorrhages associated with atherosclerotic intimal tears. Finally, a significant defense rallied by endothelium when exposed to heme is the generation of large amounts of the iron-chelating protein, ferritin. Ferritin-loaded cells are extraordinarily resistant to oxidant damage, and we hypothesize that this may be a model of cellular defense in many other disease and degenerative states as well.

Original languageEnglish (US)
Pages (from-to)114-124
Number of pages11
JournalPerspectives in Biology and Medicine
Volume38
Issue number1
DOIs
StatePublished - 1994

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