Overwhelming data from epidemiological studies and clinical trials reveal that consumption of fish oils (omega-3 polyunsaturated fatty acids) reduces cardiovascular deaths (CVD) and retards the progression of atherosclerosis in patients with coronary heart diseases. However, the cellular and molecular mechanisms by which omega-3 polyunsaturated fatty acids exert their protective effects remain poorly understood. Exciting data from the applicant's laboratory has revealed that administration of omega-3 polyunsaturated fatty acids significantly increased the phosphorylation of AMPK at Thr172 and AMPK activity. Activation of AMPK suppresses 26S proteasomes, the activation of nuclear factor kappa B, and the expression of NAD(P)H oxidase. Consistently, genetic deletion of AMPK12 in either ApoE knockout (Apo E-/-) or LDL receptor knockout (LDLr-/-) strain markedly increased 26S proteasome activity, I?B degradation, NF:B transactivation, NAD(P)H oxidase subunit overexpression, oxidative stress, endothelial dysfunction, and atherosclerosis, all of which were largely suppressed by chronic administration of MG132, a potent and cell permeable proteasome inhibitor. The central hypothesis of the current application is that selective activation of AMPK by omega-3 polyunsaturated fatty acids inhibits 26S proteasomes and NF-?B-mediated overexpression of NAD(P)H oxidase resulting in decreased oxidative stress, a key factor in vascular injury caused by high fat diets (HFD). Comprehensive experimental approaches including pharmacological and genetic means (siRNA and adenoviruses) will be used (1) to establish the essential roles of AMPK activation in omega-3 polyunsaturated fatty acids-induced suppression of NF:B-mediated aberrant expression of NAD(P)H oxidase in endothelial cells;(2) to elucidate the central roles of AMPK and 26S proteasome in omega-3 polyunsaturated fatty acids-induced inhibition on NF:B- mediated overexpression of NAD(P)H oxidase in endothelial cells;(3) to dissect the molecular mechanisms by which AMPK suppresses 26S proteasome activity, and (4) to assess the effects of AMPK on endothelial function and atherosclerosis in mice with the endothelium-specific depletion of AMPK (Tg-Cre-AMPK 11 or 12 (flox/flox), loss-of function) or in mice with the endothelium-specific overexpression of a constitutively active AMPK (Tg-CAAMPK, gain-of-function) in vivo. This powerful combination of in vitro and in vivo techniques and gain-/loss-of-function approaches will yield important insights into how omega-3 polyunsaturated fatty acids protect against cardiovascular diseases. Importantly, completion of the proposed studies will also provide novel insights into whether 26S proteasomes and AMPK are potential therapeutic targets for countering atherosclerosis associated with common diseases including aging, obesity, diabetes, and hypertension.
Overwhelming data from epidemiological studies and clinical trials reveal that consumption of fish oils and omega-3 polyunsaturated fatty acids reduces cardiovascular deaths (CVD) and retards the progression of atherosclerosis in patients with coronary heart diseases. However, the cellular and molecular mechanisms by which fish oils (omega-3 polyunsaturated fatty acids) exert their protective effects remain poorly understood. In this application, comprehensive experimental approaches will be used to test the central hypothesis that selective activation of AMPK by EPA inhibits 26S proteasomes and NF-?B-mediated overexpression of NAD(P)H oxidase resulting in decreased oxidative stress, a key factor in vascular injury caused by high fat diets (HFD). It is anticipated that the completion of this project will yield important insights into how omega-3 polyunsaturated fatty acids protect against cardiovascular diseases.
|Yu, Xi-Yong; Song, Ping; Zou, Ming-Hui (2018) Obesity Paradox and Smoking Gun: A Mystery of Statistical Confounding? Circ Res 122:1642-1644|
|Lu, Qiulun; Xie, Zhonglin; Yan, Chenghui et al. (2018) SNRK (Sucrose Nonfermenting 1-Related Kinase) Promotes Angiogenesis In Vivo. Arterioscler Thromb Vasc Biol 38:373-385|
|Liu, Zhaoyu; Zhu, Huaiping; Dai, Xiaoyan et al. (2017) Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis. Circ Res 121:1047-1057|
|Okon, Imoh; Ding, Ye; Zou, Ming-Hui (2017) Ablation of Interferon Regulatory Factor 3 Promotes the Stability of Atherosclerotic Plaques. Hypertension 69:407-408|
|Zhang, W; Ding, Y; Zhang, C et al. (2017) Deletion of endothelial cell-specific liver kinase B1 increases angiogenesis and tumor growth via vascular endothelial growth factor. Oncogene 36:4277-4287|
|Zhang, Miao; Zhu, Huaiping; Ding, Ye et al. (2017) AMP-activated protein kinase ?1 promotes atherogenesis by increasing monocyte-to-macrophage differentiation. J Biol Chem 292:7888-7903|
|Ding, Ye; Zhang, Miao; Zhang, Wencheng et al. (2016) AMP-Activated Protein Kinase Alpha 2 Deletion Induces VSMC Phenotypic Switching and Reduces Features of Atherosclerotic Plaque Stability. Circ Res 119:718-30|
|Duan, Quanlu; Ni, Li; Wang, Peihua et al. (2016) Deregulation of XBP1 expression contributes to myocardial vascular endothelial growth factor-A expression and angiogenesis during cardiac hypertrophy in vivo. Aging Cell 15:625-33|
|Dai, Xiaoyan; Ding, Ye; Liu, Zhaoyu et al. (2016) Phosphorylation of CHOP (C/EBP Homologous Protein) by the AMP-Activated Protein Kinase Alpha 1 in Macrophages Promotes CHOP Degradation and Reduces Injury-Induced Neointimal Disruption In Vivo. Circ Res 119:1089-1100|
|Okon, Imoh S; Ding, Ye; Coughlan, Kathleen A et al. (2016) Aberrant NRP-1 expression serves as predicator of metastatic endometrial and lung cancers. Oncotarget 7:7970-8|
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