Patients with diabetes suffer from increased incidence and severity of atherosclerotic cardiovascular diseases. To study the mechanisms through which diabetes accelerates vascular disease, we have identified mouse models of insulin resistance, i.e. C57BL/6 apoE-/- mice fed a fat-rich western diet and insu|in receptor and insulin receptor substrate-1 double heterozygous (IR+/-IRS1+/-) mice, which we have successfully crossed into the apolipoprotein E-deficient (apoE-/-) mouse on the C57BL/6 background. ApoE-/- mice, like humans at elevated risk for atherosclerotic cardiovascular disease, show monocyte-derived macrophages and foam cells and T-helper 1 cells (Th1) in lesions. The role B cells and other lymphocytes in diabetesaccelerated atherosclerosis is unknown. We have developed a flow cytometry-based method to analyze immune cell content of the mouse aortic wall. We propose to determine why and how atherosclerosis results in chronic inflammation of the vascular wall that does not resolve, and how insulin resistance and type 2 diabetes modify this process.
Specific aim 1 is to determine the aortic wall content of B, T, and antigen presenting cells in atherosclerotic, insulin resistant and type 2 diabetic mice and pigs. We propose to compare the composition of the aortic walls in apoE-/- mice on chow diet, apoE-/- mice on western diet (insulin resistant), IR+/- IRS1+/- mice (insulin resistant or diabetic, depending on age), and IR+/- IRS1+/- apoE-/- mice (insulin resistant and atherosclerosis-prone) with and without western diet. All these mice are on the C57BL/6 background.
Specific aim 2 is to identify the molecular mechanisms by which lymphocytes enter the artery wall in these mouse models of atherosclerosis, insulin resistance, T2D or both. We will use short-term homing assays using fluorescently labeled splenocytes from various knockout mice and long-term homing assays using green fluorescent protein (GFP)-expressing splenocytes.
Specific aim 3 is to directly investigate the mechanisms by which lymphocytes interact with the endothelium in carotid and femoral arteries of apoE-/- mice with and without insulin resistance/T2D in vivo. Molecular insights from these intravital microscopy studies and the homing studies described in aim 2 will guide the generation pf double knockout mice and the design of antibody blocking experiments. Disease outcome will be assessed by mapping lesion sizes en face and in cross sections by histology and immunostaining. Together with the other projects described in this PPG renewal application, we expect that our cumulative research will impact the understanding and treatment of diabetic cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
7P01HL055798-15
Application #
8098767
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
15
Fiscal Year
2010
Total Cost
$280,037
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Jeong, Se-Jin; Kim, Sinai; Park, Jong-Gil et al. (2018) Prdx1 (peroxiredoxin 1) deficiency reduces cholesterol efflux via impaired macrophage lipophagic flux. Autophagy 14:120-133
Gao, Chuan; Tabb, Keri L; Dimitrov, Latchezar M et al. (2018) Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS). Sci Rep 8:5603
Gaddis, Dalia E; Padgett, Lindsey E; Wu, Runpei et al. (2018) Apolipoprotein AI prevents regulatory to follicular helper T cell switching during atherosclerosis. Nat Commun 9:1095
Que, Xuchu; Hung, Ming-Yow; Yeang, Calvin et al. (2018) Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice. Nature 558:301-306
Senders, Max L; Que, Xuchu; Cho, Young Seok et al. (2018) PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis. J Am Coll Cardiol 71:321-335
Thomas, Graham D; Hamers, Anouk A J; Nakao, Catherine et al. (2017) Human Blood Monocyte Subsets: A New Gating Strategy Defined Using Cell Surface Markers Identified by Mass Cytometry. Arterioscler Thromb Vasc Biol 37:1548-1558
Nowyhed, Heba N; Chandra, Shilpi; Kiosses, William et al. (2017) ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content. Sci Rep 7:40273
Byun, Young Sup; Yang, Xiaohong; Bao, Weihang et al. (2017) Oxidized Phospholipids on Apolipoprotein B-100 and Recurrent Ischemic Events Following Stroke or Transient Ischemic Attack. J Am Coll Cardiol 69:147-158
Torzewski, Michael; Ravandi, Amir; Yeang, Calvin et al. (2017) Lipoprotein(a) Associated Molecules are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis. JACC Basic Transl Sci 2:229-240
Moriarty, Patrick M; Varvel, Stephen A; Gordts, Philip L S M et al. (2017) Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype: An Analysis of 431?239 Patients. Arterioscler Thromb Vasc Biol 37:580-588

Showing the most recent 10 out of 217 publications