Cholate-Containing High-Fat Diet Induces the Formation of Multinucleated Giant Cells in Atherosclerotic Plaques of Apolipoprotein E−/− Mice

OBJECTIVE: To determine the role of multinucleated giant cells (MGCs) in cardiovascular diseases. METHODS AND RESULTS: MGCs are a hallmark of giant cell arteritis. They are also described in atherosclerotic plaques from aortic aneurysms and carotid and coronary arteries. Herein, we demonstrate that the cholate-containing Paigen diet yields many MGCs in atherosclerotic plaques of apolipoprotein E-/- mice. These mice revealed a 4-fold increase in MGC numbers when compared with mice on a Western or Paigen diet without cholate. Most of the MGCs stained intensively for cathepsin K and were located at fibrous caps and close to damaged elastic laminae, with associated medial smooth muscle cell depletion. During in vitro experiments, MGCs demonstrated a 6-fold increase in elastolytic activity when compared with macrophages and facilitated transmigration of smooth muscle cells through a collagen-elastin matrix. An elastin-derived hexapeptide (Val-Gly-Val-Ala-Pro-Gly [VGVAPG]) significantly increased the rate of macrophage fusion, providing a possible mechanism of in vivo MGC formation. Comparable to the mouse model, human specimens from carotid arteries and aortic aneurysms contained cathepsin K-positive MGCs. CONCLUSIONS: Apolipoprotein E-/- mice fed a Paigen diet provide a model to analyze the tissue-destructive role of MGCs in vascular diseases.