Inducible Apoe Gene Repair in Hypomorphic ApoE Mice Deficient in the Low-Density Lipoprotein Receptor Promotes Atheroma Stabilization With a Human-Like Lipoprotein Profile
Objective—To study atherosclerosis regression in mice after plasma lipid reduction to moderately elevated apolipoprotein B (apoB)–lipoprotein levels.
Approach and Results—Chow-fed hypomorphic Apoe mice deficient in low-density lipoprotein receptor expression (Apoeh/hLdlr–/–Mx1-cre mice) develop hyperlipidemia and atherosclerosis. These mice were studied before and after inducible cre-mediated Apoe gene repair. By 1 week, induced mice displayed a 2-fold reduction in plasma cholesterol and triglyceride levels and a decrease in the non–high-density lipoprotein:high-density lipoprotein-cholesterol ratio from 87%:13% to 60%:40%. This halted atherosclerotic lesion growth and promoted macrophage loss and accumulation of thick collagen fibers for ≤8 weeks. Concomitantly, blood Ly-6Chi monocytes were decreased by 2-fold but lesional macrophage apoptosis was unchanged. The expression of several genes involved in extracellular matrix remodeling and cell migration was changed in lesional macrophages 1 week after Apoe gene repair. However, mRNA levels of numerous genes involved in cholesterol efflux and inflammation were not significantly changed at this time point.
Conclusions—Restoring apoE expression in Apoeh/hLdlr–/–Mx1-cre mice resulted in lesion stabilization in the context of a human-like ratio of non–high-density lipoprotein:high-density lipoprotein-cholesterol. Our data suggest that macrophage loss derived in part from reduced blood Ly-6Chi monocytes levels and genetic reprogramming of lesional macrophages.
- Received July 23, 2012.
- Accepted April 19, 2013.
- © 2013 American Heart Association, Inc.