Evolution and Stabilization of Vulnerable Atherosclerotic Plaques

We studied a recently recognized signaling system known as CD154, a transmembrane protein

Peter Libby


Scholarcy highlights

  • Human coronary arteries, unlike those in most other mammals, have resident smooth muscle cells in the tunica intima underneath the endothelial monolayer, even before atherosclerotic changes begin. The thickness of the intimal layer increases progressively as humans age from fetus to child to young adult, and its complex structure probably favors the formation of atheroma
  • Work with experimental atherosclerosis has yielded information that implicates vascular cell adhesion molecule-1 in the adhesion reaction, among other adhesion molecules; shows that monocyte chemoattractant protein-1 is a potent chemoattractant that causes the directed migration of leukocytes; and shows that macrophage colony stimulating factor is a co-mitogen and activator that can cause the expression of scavenger receptors on macrophages
  • We first examined how lipid lowering by diet alone affects the rabbit atheroma in order to determine the effects of lipid lowering independent of the action of drugs5. 8,72–75 We chose cholesterol-fed rabbits as a model because rabbit atheroma resembles ‘vulnerable’ plaques of the human coronary artery, especially when high-cholesterol feeding is combined with mechanical injury
  • Kockx et al demonstrated a similar finding of decreased inflammation and increased collagen in rabbit atheroma during dietary lipid lowering7.9 Tissue factor expression and activity declined strikingly in association with reduced CD154 and CD407.3 This series of experimental observations suggest that in rabbits with dietinduced atherosclerosis, reduced cholesterol consumption could limit inflammation and improve those features of plaque that are associated with instability and thrombogenicity in humans
  • Endothelial cell activation contributes to infiltration of inflammatory cells in atheroma1.4,15 Oxidative stress may play an important role in the pathogenesis of inflammatory diseases, including atherosclerosis, and we have recently found that dietary lipid lowering can reduce oxidative stress and endothelial cell activation in rabbit atheroma7.5 Such findings on endothelial and smooth muscle cell activation should improve our understanding of mechanisms underlying the clinical outcomes observed with lipidlowering therapy
  • Why do coronary events still occur in patients who undergo aggressive lipid-lowering therapy? Are matrix metalloproteinase really key players in plaque disruption? Why do some hypercholesterolemic patients have thrombotic complications, and others do not? Further studies employing new technologies may clarify more precisely the mechanisms of vascular inflammation and provide novel therapies

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