This application will examine a distinct atherosclerosis pathology to understand the cause of the exacerbated lesions found in the abdominal aorta of hyperlipidemic mice challenged with a chronic, systemic proinflammatory stimulus. When hypercholesterolemic Low Density Lipoprotein receptor knockout (LDLr-/-) mice are exposed multiple times to a potent Toll-Like Receptor (TLR) agonist, lesions within the abdominal aorta are severe;whereas lesions within the thoracic aorta are minimal. We will test the hypothesis that differences in the inflammatory characteristics of adipose tissue surrounding the thoracic versus the abdominal aorta account for the regional differences in atherosclerosis severity. The chronic inflammation disease model is an LDLr-/- mouse fed a high fat diet (HFD) and repeatedly exposed to the synthetic TLR2/1 agonist, Pam3.
In Aim 1 thoracic and abdominal aortic tissue segments of Pam3 injected mice will be compared to comparable tissue segments from mice exposed to a vehicle control. Gene expression and cytokine (including adipokine) production will be examined in tissue segments and in multiple cells within adipose tissues including adipocytes, macrophages, dendritic cells, leukocytes, endothelial cells and fibroblasts. Isolated abdominal vascular stromal fraction cells will be co cultured with minced thoracic adipose tissues embedded in a collagenase gel. This data should support the hypothesis that the environment within thoracic periaortic adipose tissue is functionally different from the pro inflammatory setting of the periaortic abdominal adipose tissue.
Aim 2 will test the hypothesis that TLR2/1 expressing bone marrow-derived cells are essential for the inflammation induced severe abdominal atherosclerosis seen in HFD fed and Pam3 exposed LDLr-/- mice. This idea will be tested by performing bone marrow transplantation of LDLr-/- mice with bone marrow donors from LDLr-/-TLR2-/- double mutant mice and LDLr-/- control mice. Inflammation and aortic atherosclerosis progression will be examined.
Aim 3 will test the hypothesis that this adipose tissue inflammation can be prevented. Peroxisome proliferator-activated nuclear receptor gamma (PPAR?) activation in unilocular adipocytes within adipose tissue should promote the production of adiponectin that will mitigate inflammation and reduce disease.
This aim will utilize TLR agonist exposed transgenic mice that constitutively express normal levels of PPAR? in only adipocytes.
The third aim will provide mechanistic insight into inflammation- induced severe abdominal disease. Collectively, these studies will provide key insight into an extreme atherosclerosis pathology linked to systemic inflammation resulting from chronic exposure to tissue injury, infectious agents and pathogens.

Public Health Relevance

Atherosclerosis is a major health problem. Obesity, a major risk factor for atherosclerosis, is increasing in Western societies. This application will directly study a link between obesity and the chronic inflammation that promotes atherosclerosis progression leading to heart disease and stroke.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Kirby, Ruth
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Scripps Research Institute
La Jolla
United States
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Curtiss, Linda K; Black, Audrey S; Bonnet, David J et al. (2012) Atherosclerosis induced by endogenous and exogenous toll-like receptor (TLR)1 or TLR6 agonists. J Lipid Res 53:2126-32