Key result
Exposure to oxidized LDL and monocytes significantly increased the destabilization of calcific nodules via induction of matrix metalloproteinases, an effect reversed by MMP inhibition.
This study establishes a novel in vitro and in vivo model of vulnerable plaque, demonstrating that calcific nodules are destabilized by oxidized lipids and monocytes through MMP induction.
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Provides novel animal model of vulnerable calcific plaque; leaves open MMP inhibition for human plaque stabilization.
Vulnerable plaque remains clinically undetectable, and there is no accepted in vitro model. We characterize the calcific nodules produced by calcifying vascular cells (CVC) in ApoE-null mice, demonstrating increased destabilization of cultured nodules in the presence of oxidized low-density lipoprotein (oxLDL) and monocytes under pulsatile shear stress. CVC implanted in the subcutaneous space of hyperlipidemic mice produced nodules revealing features of calcific atherosclerotic plaque including a fibrous cap, cholesterol clefts, thin shoulder, lipids, and calcium mineral deposits. CVC nodules seeded in the pulsatile flow channel (τ(avg) = 23 dyn/cm(2), ∂τ/∂t = 71 dyn·cm(-2)·s(-1)) underwent deformation and destabilization. Computational fluid dynamics revealed distinct shear force profiles on the nodules. Presence of oxLDL or monocytic THP-1 cells significantly increased the numbers of nodules destabilized from the substrate. Both oxLDL and THP-1 increased matrix metalloproteinase (MMP) activity in CVC. The MMP inhibitor GM6001 significantly reversed oxLDL- and THP-1-induced nodule destabilization, whereas overexpression of MMP-9 increased destabilization. These findings demonstrate that CVC-derived nodules resembled calcific atherosclerotic plaque and were destabilized in the presence of active lipids and monocytes via induction of MMPs.
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Li et al. (2011) studied Vulnerable plaque. Oxidized low-density lipoprotein (oxLDL) and monocytes vs. Absence of oxLDL/monocytes or presence of MMP inhibitor GM6001 was evaluated on Nodule destabilization and matrix metalloproteinase (MMP) activity. Exposure to oxidized LDL and monocytes significantly increased the destabilization of calcific nodules via induction of matrix metalloproteinases, an effect reversed by MMP inhibition.
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