title: Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice.
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.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, New York University Langone Medical Center, New York, New York 10016, United States of America.
authors.forename: Florian
authors.initials: F
authors.lastname: Willecke
authors.affiliation: Division of Cardiology, New York University Langone Medical Center, New York, New York 10016, United States of America.
authors.forename: Chujun
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, United States of America.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Oka
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, United States of America.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, New York University Langone Medical Center, New York, New York 10016, United States of America.
authors.forename: Yunying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington 98109, United States of America.
authors.forename: Shelley
authors.initials: S
authors.lastname: Barnhart
authors.affiliation: Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington 98109, United States of America.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Bornfeldt
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, New York University Langone Medical Center, New York, New York 10016, United States of America.
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.affiliation: Division of Cardiology, New York University Langone Medical Center, New York, New York 10016, United States of America.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000473:pathology; D059305:Diet, High-Fat; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006943:Hyperglycemia / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D007333:Insulin Resistance; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*; D013311:Streptozocin
chemical_list: D002791:Cholesterol, Dietary; D011973:Receptors, LDL; D013311:Streptozocin; D003094:Collagen