Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis
Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL
Receptor-Deficient Mice.
Authors Willecke F, Yuan C, Oka K, Chan L, Hu Y, Barnhart S, Bornfeldt KE, Goldberg IJ,
Fisher EA
Submitted By Edward Fisher on 7/7/2015
Status Published
Journal PLoS ONE
Year 2015
Date Published
Volume : Pages 10 : e0128996
PubMed Reference 26046657
Abstract We tested whether a high fat diet (HFD) containing the inflammatory dietary
fatty acid palmitate or insulin deficient diabetes altered the remodeling of
atherosclerotic plaques in LDL receptor knockout (Ldlr-/-) mice. Cholesterol
reduction was achieved by using a helper-dependent adenovirus (HDAd) carrying
the gene for the low-density lipoprotein receptor (Ldlr; HDAd-LDLR). After
injection of the HDAd-LDLR, mice consuming either HFD, which led to insulin
resistance but not hyperglycemia, or low fat diet (LFD), showed regression
compared to baseline. However there was no difference between the two groups in
terms of atherosclerotic lesion size, or CD68+ cell and lipid content. Because
of the lack of effects of these two diets, we then tested whether viral-mediated
cholesterol reduction would lead to defective regression in mice with greater
hyperglycemia. In both normoglycemic and streptozotocin (STZ)-treated
hyperglycemic mice, HDAd-LDLR significantly reduced plasma cholesterol levels,
decreased atherosclerotic lesion size, reduced macrophage area and lipid
content, and increased collagen content of plaque in the aortic sinus. However,
reductions in anti-inflammatory and ER stress-related genes were less pronounced
in STZ-diabetic mice compared to non-diabetic mice. In conclusion, HDAd-mediated
Ldlr gene therapy is an effective and simple method to induce atherosclerosis
regression in Ldlr-/- mice in different metabolic states.

Investigators with authorship
Karin BornfeldtUniversity of Washington
Edward FisherNew York University School of Medicine
Ira GoldbergNew York University School of Medicine