Oxidant resistant human apolipoprotein A-I functions similarly to the unmodified human isoform in delaying atherosclerosis progression and promoting atherosclerosis regression in hyperlipidemic mice

• Published in: PloS one Vol. 17; no. 2; p. e0259751
• Main Authors: Opoku, Emmanuel, Berisha, Stela, Brubaker, Gregory, Robinet, Peggy, Smith, Jonathan D.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.02.2022; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Apolipoprotein A; Apolipoprotein A-I; Apolipoprotein A-I - genetics; Apolipoprotein A-I - metabolism; Apolipoproteins; Arteriosclerosis; Atherosclerosis; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biology and Life Sciences; Care and treatment; Cholesterol; Chromatography; Comparative analysis; Complications and side effects; Diet; Disease Models, Animal; Disease Progression; Ecology and Environmental Sciences; Engineering and Technology; Female; Females; Health aspects; High density lipoprotein; Humans; Hyperlipidemia; Hyperlipidemias - metabolism; Isoforms; Laboratory animals; Lesions; Low density lipoprotein; Low fat diet; Male; Males; Medicine and Health Sciences; Metabolism; Mice; Mice, Knockout; Mice, Transgenic; Nutrient deficiency; Oxidants; Oxidants - metabolism; Oxidation; Oxidizing agents; Peroxidase; Peroxidase - metabolism; Physical Sciences; Plasma; Protein Isoforms - metabolism; Proteins; Receptors, LDL - genetics; Receptors, LDL - metabolism; Regression; Regression analysis; Research and Analysis Methods; Risk factors; Rodents; Sex differences; Transgenic animals; Transgenic mice; Triglycerides; United States; United States > US; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0259751

Transgenic overexpression of apolipoprotein A-I (apoA1) has been shown to delay atherosclerosis lesion progression and promote lesion regression in mouse models; however, apoA1 is subject to oxidation by myeloperoxidase (MPO) and loss of function. The activity of oxidant resistant human apoA1 was compared to unmodified human apoA1 in mouse models of atherosclerosis progression and regression. Human apoA1 and the MPO oxidant resistant 4WF isoform transgenic mice were bred to LDL receptor deficient (LDLr KO) mice and fed a western-type diet. High level expression of these human apoA1 isoforms did not lead to increased HDL-cholesterol levels on the LDLr KO background. In males and females, lesion progression was studied over time, and both apoA1 and 4WF transgenic mice vs. LDLr KO mice had significant and similar delayed lesion progression and reduced non-HDL cholesterol. Using time points with equivalent lesion areas, lesion regression was initiated by feeding the mice a low-fat control diet containing a microsomal triglyceride transfer protein inhibitor for 7 weeks. Lesions regressed more in the male apoA1 and 4WF transgenics vs. the LDLr KO, but the 4WF isoform was not superior to the unmodified isoform in promoting lesion regression. Both human apoA1 and the 4WF MPO oxidant resistant apoA1 isoform delayed lesion progression and promoted lesion regression in LDLr KO mice, with more pronounced effects in males than females; moreover, the 4WF isoform functioned similarly to the unmodified human apoA1 isoform.