Complications from atherosclerosis represent a major cause of morbidity and mortality in Western society. The accumulation of low-density lipoprotein (LDL)-derived cholesterol and inflammatory cells in the artery wall are the initiating events that cause atherosclerosis. However, the factors that underlie the initiation of atherosclerosis are still poorly understood. Our recent data suggest that one such factor may be caveolin-1 (Cav-1), an important structural component of caveolae. Caveolae are 50-100 nm flask-shaped invaginations of plasma membrane, and Cav-1 is essential for caveolae biogenesis in several tissues, including the arterial endothelium. Physiologically, the loss of caveolae results in impairment of cholesterol homeostasis, insulin resistance, nitric oxide production (NO), and defects in cardiopulmonary and vascular function. Interestingly, mice deficient in Cav-1 exhibit resistance to atherosclerosis despite a marked proatherogenic lipid profile, suggesting that Cav-1 determines the athero-susceptibility to the vessel wall. We recently demonstrated the critical role of endothelial Cav-1 during the progression of atherosclerosis in mice. Mice were generated lacking Cav-1 and ApoE but expressing endothelial-specific Cav-1 in the double knockout background (ApoE-/-Cav-1REC). Genetic ablation of Cav-1 on the ApoE knockout background inhibited the progression of atherosclerosis, while re-expression of Cav-1 in the endothelium promoted lesion expansion. Several different mechanism appear to be involved, including reduced LDL infiltration into the artery wall, increased production of nitric oxide (NO), reduced expression of leukocyte adhesion molecules and decreased monocyte accumulation in atherosclerotic plaques. The precise mechanisms by which Cav-1 and/or caveolae controls all of these events remains unknown. Thus, a major challenge of this grant proposal is to determine the molecular mechanism by which endothelial-specific Cav-1 controls the early stages and progression of atherosclerosis. We propose three aims.
Aim 1 : To investigate the molecular mechanism by which Cav-1 regulates lipoprotein trafficking in the artery wall and lipid/lipoprotein metabolism in arterial endothelial cells.
Aim 2 : To define the role of NO in the atheroprotection observed in Cav-1 null mice.
Aim 3 : To define whether Cav-1 expression regulates EC inflammatory response and macrophage mobilization in vivo. In summary completion of these aims will provide insight into fundamental regulatory mechanism by which Cav-1/caveolae regulates lipoprotein metabolism and the progression of atherosclerosis.

Public Health Relevance

The accumulation of low-density lipoprotein (LDL)-derived cholesterol and inflammatory cells in the artery wall are the initiating events that cause atherosclerosis. Our recent data suggest that one such factor may be caveolin-1 (Cav-1), an important structural component of caveolae. The proposal main goal is to investigate the mechanism by which Cav-1 regulates lipoprotein metabolism and the progression of atherosclerosis. This work will provide critical insight into fundamental regulatory mechanism and may indentify potential therapeutic strategies for the regulation of the lipoprotein and inflammatory cell infiltration in the artery wall through modulation of Cav-1 expression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106063-02
Application #
8220824
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2011-02-04
Project End
2016-01-31
Budget Start
2012-02-14
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$422,500
Indirect Cost
$172,500
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Aryal, Binod; Rotllan, Noemi; Fernández-Hernando, Carlos (2014) Noncoding RNAs and atherosclerosis. Curr Atheroscler Rep 16:407
Goedeke, Leigh; Fernández-Hernando, Carlos (2014) MicroRNAs: a connection between cholesterol metabolism and neurodegeneration. Neurobiol Dis 72 Pt A:48-53
Sala, Federica; Aranda, Juan F; Rotllan, Noemi et al. (2014) MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr-/-mice. Thromb Haemost 112:796-802
Price, Nathan L; Ramírez, Cristina M; Fernández-Hernando, Carlos (2014) Relevance of microRNA in metabolic diseases. Crit Rev Clin Lab Sci 51:305-20
Canfran-Duque, Alberto; Pastor, Oscar; Quintana-Portillo, Rocio et al. (2014) Curcumin promotes exosomes/microvesicles secretion that attenuates lysosomal cholesterol traffic impairment. Mol Nutr Food Res 58:687-97
Araldi, Elisa; Chamorro-Jorganes, Aranzazu; van Solingen, Coe et al. (2013) Therapeutic Potential of Modulating microRNAs in Atherosclerotic Vascular Disease. Curr Vasc Pharmacol :

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