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 #
1R01HL106063-01
Application #
8023626
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
2011-02-04
Budget End
2012-01-31
Support Year
1
Fiscal Year
2011
Total Cost
$422,500
Indirect Cost
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
Willeit, Peter; Skroblin, Philipp; Moschen, Alexander R et al. (2017) Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes. Diabetes 66:347-357
Price, Nathan L; Rotllan, Noemi; Canfrán-Duque, Alberto et al. (2017) Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis. Cell Rep 21:1317-1330
Canfrán-Duque, Alberto; Rotllan, Noemi; Zhang, Xinbo et al. (2017) Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO Mol Med 9:1244-1262
Zhang, Xinbo; Fernández-Hernando, Carlos (2017) miR-33 Regulation of Adaptive Fibrotic Response in Cardiac Remodeling. Circ Res 120:753-755
Araldi, Elisa; Fernández-Fuertes, Marta; Canfrán-Duque, Alberto et al. (2017) Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages. Cell Rep 19:2743-2755
Price, Nathan L; Fernández-Hernando, Carlos (2016) miRNA regulation of white and brown adipose tissue differentiation and function. Biochim Biophys Acta 1861:2104-2110
Pauta, Montse; Rotllan, Noemi; Fernández-Hernando, Ana et al. (2016) Akt-mediated foxo1 inhibition is required for liver regeneration. Hepatology 63:1660-74
Aryal, Binod; Rotllan, Noemi; Araldi, Elisa et al. (2016) ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression. Nat Commun 7:12313
Chamorro-Jorganes, Aránzazu; Lee, Monica Y; Araldi, Elisa et al. (2016) VEGF-Induced Expression of miR-17-92 Cluster in Endothelial Cells Is Mediated by ERK/ELK1 Activation and Regulates Angiogenesis. Circ Res 118:38-47
Canfrán-Duque, Alberto; Lin, Chin-Sheng; Goedeke, Leigh et al. (2016) Micro-RNAs and High-Density Lipoprotein Metabolism. Arterioscler Thromb Vasc Biol 36:1076-84

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