Atherosclerosis and its complications remain leading causes of death and disability in the United States. Although promoting the regression of atherosclerosis has emerged as a promising treatment strategy for atherosclerosis, the molecular and cellular mechanisms that orchestrate this clinically relevant process are poorly understood. Moreover, the mechanisms by which the apolipoprotein 4 (apoE4) allele predisposes to symptomatic forms of atherosclerosis and whether it can impair its regression following plasma lipid lowering, remains largely unknown. To fill these gaps of knowledge, we propose a series of experiments with genetically engineered murine models of apoE4, conditional apoE expression, reversible hyperlipidemia, and atherosclerosis regression developed in our laboratory. Hypomorphic ApoeR61h/h mice express reduced levels of an apoE4-like form of murine apoE (Arg-61 apoE) that reproduces a unique biophysical feature of human apoE4 called """"""""domain interaction"""""""". Our previous studies have shown that domain interaction in Arg- 61 apoE is sufficient to reproduce the VLDL-binding preference of human apoE4 in hyperlipidemic mouse plasma. Moreover, our studies of conditional expression of apoE in ApoeR61h/h mice has recently established the existence of a role for apoE in promoting the regression of atherosclerosis beyond lowering plasma cholesterol levels. Experiments detailed in this proposal will make use of ApoeR61h/h mice, as well as new variants of this model, to investigate mechanisms by which apoE accumulation in plasma and macrophage-derived apoE in lesions regulate the onset and progression of atherosclerosis in the setting of hyperlipidemia. We will also test the hypothesis that apoE4 domain interaction in Arg-61 apoE will accelerate the progression of atherosclerosis and impair its regression following sustained lipid lowering. Lastly, we will test the hypothesis that apoE expression levels influence the migration of monocytes into established lesions, and the egress of macrophages from lesions during the regression of atherosclerosis in an isoform-specific manner. Our long term goal is to clarify the molecular and cellular mechanisms by which apoE isoforms regulate the progression and regression of atherosclerosis. A better understanding of these mechanisms would help usher in a new generation of molecular therapies to fight atherosclerosis, particularly among apoE4 carriers who represent 20% of the global population.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Hasan, Ahmed AK
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Northern California Institute Research & Education
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Luk, Fu Sang; Kim, Roy Y; Li, Kang et al. (2016) Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis. J Cardiovasc Pharmacol 67:47-56
Li, Kang; Ching, Daniel; Luk, Fu Sang et al. (2015) Apolipoprotein E enhances microRNA-146a in monocytes and macrophages to suppress nuclear factor-?B-driven inflammation and atherosclerosis. Circ Res 117:e1-e11
Mattis, Aras N; Song, Guisheng; Hitchner, Kelly et al. (2015) A screen in mice uncovers repression of lipoprotein lipase by microRNA-29a as a mechanism for lipid distribution away from the liver. Hepatology 61:141-52
Wang, Guanying; Kim, Roy Y; Imhof, Isabella et al. (2014) The immunosuppressant FTY720 prolongs survival in a mouse model of diet-induced coronary atherosclerosis and myocardial infarction. J Cardiovasc Pharmacol 63:132-143
Gaudreault, Nathalie; Kumar, Nikit; Olivas, Victor R et al. (2013) Hyperglycemia impairs atherosclerosis regression in mice. Am J Pathol 183:1981-1992
Lovett, David H; Mahimkar, Rajeev; Raffai, Robert L et al. (2013) N-terminal truncated intracellular matrix metalloproteinase-2 induces cardiomyocyte hypertrophy, inflammation and systolic heart failure. PLoS One 8:e68154
Eberlé, Delphine; Luk, Fu Sang; Kim, Roy Y et al. (2013) Inducible ApoE gene repair in hypomorphic ApoE mice deficient in the low-density lipoprotein receptor promotes atheroma stabilization with a human-like lipoprotein profile. Arterioscler Thromb Vasc Biol 33:1759-67
Raffai, Robert L (2012) Apolipoprotein E regulation of myeloid cell plasticity in atherosclerosis. Curr Opin Lipidol 23:471-8
Eberlé, Delphine; Kim, Roy Y; Luk, Fu Sang et al. (2012) Apolipoprotein E4 domain interaction accelerates diet-induced atherosclerosis in hypomorphic Arg-61 apoe mice. Arterioscler Thromb Vasc Biol 32:1116-23
Gaudreault, Nathalie; Kumar, Nikit; Olivas, Victor R et al. (2012) Macrophage-specific apoE gene repair reduces diet-induced hyperlipidemia and atherosclerosis in hypomorphic Apoe mice. PLoS One 7:e35816

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