Diabetes promotes atherosclerosis in humans, greatly increasing the risk of developing cardiovascular disease. Compelling clinical data show that improving glycemic control early in life has long-term beneficial effects on cardiovascular events in human subjects with type 1 diabetes. Macrophages are likely to play a key role in the stimulatory effects of diabetes on atherosclerosis. Our preliminary studies demonstrate that in addition to stimulating a pro-inflammatory response, diabetes and elevated glucose levels lead to an increased expression of an enzyme that esterifies fatty acids (long-chain acyl-CoA synthetase 1;ACSL1) in macrophages, suggesting a close connection between the inflammatory capacity and ACSL1 in macrophages, diabetes and states of hyperglycemia. Strikingly, the stimulatory effects of diabetes on atherosclerotic lesion formation can be completely prevented by deleting ACSL1 in myeloid cells. No such effect is seen in non-diabetic mice, suggesting that the discovered mechanism is selective for diabetes. The protective effect of ACSL1-deficiency correlates with a reduced release of pro-inflammatory mediators from macrophages. The overall hypothesis of this project is that diabetes promotes atherosclerosis largely through increased glucose uptake in macrophages, which promotes an inflammatory macrophage phenotype that requires ACSL1. Our goal for the proposed project is to address two questions: 1). Does increased glucose uptake in macrophages enhance their pro-inflammatory capacity and atherosclerosis through a mechanism that requires ACSL1?;2). What is the ACSL1-dependent mechanism of glucose-mediated macrophage activation?

Public Health Relevance

These studies will increase our understanding of the molecular and cellular mechanisms involved in diabetes- accelerated atherosclerosis and cardiovascular disease. Identification of such mechanisms might help develop treatment strategies to target cardiovascular complications, and other complications, associated with diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062887-15
Application #
8690131
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Ershow, Abby
Project Start
1998-09-30
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Shimizu-Albergine, Masami; Van Yserloo, Brian; Golkowski, Martin G et al. (2016) SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP. Proc Natl Acad Sci U S A 113:E5685-93
Bornfeldt, Karin E (2016) Does Elevated Glucose Promote Atherosclerosis? Pros and Cons. Circ Res 119:190-3
Kanter, Jenny E; Bornfeldt, Karin E (2016) Impact of Diabetes Mellitus. Arterioscler Thromb Vasc Biol 36:1049-53
Manichaikul, Ani; Wang, Xin-Qun; Zhao, Wei et al. (2016) Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis. J Lipid Res 57:433-42
Libby, Peter; Bornfeldt, Karin E; Tall, Alan R (2016) Atherosclerosis: Successes, Surprises, and Future Challenges. Circ Res 118:531-4
Tabas, Ira; Bornfeldt, Karin E (2016) Macrophage Phenotype and Function in Different Stages of Atherosclerosis. Circ Res 118:653-67
Rune, Ida; Rolin, Bidda; Larsen, Christian et al. (2016) Modulating the Gut Microbiota Improves Glucose Tolerance, Lipoprotein Profile and Atherosclerotic Plaque Development in ApoE-Deficient Mice. PLoS One 11:e0146439
Vallerie, Sara N; Bornfeldt, Karin E (2015) Metabolic Flexibility and Dysfunction in Cardiovascular Cells. Arterioscler Thromb Vasc Biol 35:e37-42
Bornfeldt, Karin E (2015) Uncomplicating the Macrovascular Complications of Diabetes: The 2014 Edwin Bierman Award Lecture. Diabetes 64:2689-97
Pamir, Nathalie; Liu, Ning-Chun; Irwin, Angela et al. (2015) Granulocyte/Macrophage Colony-stimulating Factor-dependent Dendritic Cells Restrain Lean Adipose Tissue Expansion. J Biol Chem 290:14656-67

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