Atherosclerotic vascular disease remains the leading cause of death in the United States with the majority of mortality due to coronary artery disease and myocardial infarction. Risk factor modification such as reductions in hyperlipidemia constitutes the only treatment strategy available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes that provide mechanistic insight. Recent reports f the proatherogenic phenotype of mice with a macrophage-specific autophagy deficiency has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique role of processing both exogenous material such as excess atherogenic lipids and endogenous cargo that includes dysfunctional proteins and organelles. Since little is known about the effect of an atherogenic environment on macrophage lysosomes, we aimed to test the notion that lysosomal dysfunction is the product of lipid metabolism and evaluate novel ways to ameliorate this effect. Our preliminary data demonstrate that macrophages develop features of lysosome dysfunction upon exposure to atherogenic lipids. In turn, this lysosomal stress can activate TFEB, the only known transcription factor that can broadly stimulate lysosomal biogenesis and function. The regulation of macrophage TFEB appears to be critically linked to mTOR signaling, buttressed by the observation that the classic mTOR inhibitor Rapamycin can induce lysosomal biogenesis while reducing macrophage dysfunction and atherosclerosis. Understanding the links between lipid metabolism and lysosomal biogenesis has important implications in understanding plaque progression. We propose to test the hypothesis that macrophage lysosomal biogenesis mediated by the transcription factor TFEB is an important compensatory response during atherosclerosis and serves an atheroprotective role. A variety of mouse models capable of dissecting the role of TFEB action in macrophages will serve as the research tools to address this hypothesis both in vitro and in vivo.

Public Health Relevance

Progressive plaque formation, or atherosclerosis, is the pathogenic mediator of the vast majority of cardiovascular diseases and is primarily caused by an inability of the vascular system to handle increased circulating lipid. Macrophages are cells that specialize in removing the excess lipids and other debris present in the plaque. We have found that macrophages have the ability to augment their degradation machinery and propose to study the underlying mechanisms with the goal of learning how to reduce the accumulation of toxic materials that cause atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125838-02
Application #
8962169
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Chen, Jue
Project Start
2014-11-04
Project End
2019-10-31
Budget Start
2015-11-01
Budget End
2016-10-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Sergin, Ismail; Bhattacharya, Somashubhra; Emanuel, Roy et al. (2016) Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis. Sci Signal 9:ra2
Leng, Shuilong; Iwanowycz, Stephen; Saaoud, Fatma et al. (2016) Ursolic acid enhances macrophage autophagy and attenuates atherogenesis. J Lipid Res 57:1006-16
Razani, Babak; Raines, Elaine W (2015) Can the DNA damage response be harnessed to modulate atherosclerotic plaque phenotype? Circ Res 116:770-3
Sergin, Ismail; Evans, Trent D; Razani, Babak (2015) Degradation and beyond: the macrophage lysosome as a nexus for nutrient sensing and processing in atherosclerosis. Curr Opin Lipidol 26:394-404