TY - JOUR
T1 - Vascular shear forces and atherogenesis
T2 - Roles of shear-provoked endothelial viral infection and heme iron accumulation
AU - Jacob, H. S.
PY - 1994
Y1 - 1994
N2 - 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.
AB - 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.
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U2 - 10.1353/pbm.1994.0011
DO - 10.1353/pbm.1994.0011
M3 - Review article
C2 - 7997354
AN - SCOPUS:0028152655
SN - 0031-5982
VL - 38
SP - 114
EP - 124
JO - Perspectives in Biology and Medicine
JF - Perspectives in Biology and Medicine
IS - 1
ER -