Abdominal aortic aneurysm (AAAs) is the most common form of aortic aneurysm and ruptured AAAs cause at least 15,000 deaths each year in the US. Epidemical studies suggest that cigarette smoke increases the risk of AAAs 7.6-fold. However, a causative link between cigarette smoke and AAAs has not been established in human or animals. Our exciting preliminary data indicate that acute infusion of nicotine resulted in significantly increased elastin degradation, enlargement of the aorta, abnormal expression and activation of matrix metalloproteinase 2 (MMP2), and an increased incidence of AAA in ApoE knockout (ApoE-/-) mice. Importantly, we find that genetic deletion of AMP-activated protein kina (AMPK?2) markedly reduces the incidence of AAA caused by nicotine or AngII in vivo. Biochemical and biological analysis reveal that phosphorylation of AP-2? by AMPK?2 increases its binding to the MMP2 promoter resulting in transcription of pro-MMP2 and conversion into active MMP2. Thus, Thus, we hypothesize that the activation of AMPK?2 by nicotine in cigarette smoke instigates AAAs by the induction of MMP2 leading to subsequent damage of the vessel wall matrix. We will first establish if AMPK?2 is required for nicotine-instigated destruction of the vessel wall and aneurysm formation in mice in vivo. After that, we will investigate if nicotine via AMPK?2 causes aberrant expression of MMP2 and if MMP2 is responsible for nicotine-enhanced damage of the vessel wall matrix in mice in vivo. Finally, we will elucidate molecular mechanisms by which nicotine and cigarette smoke activates AMPK and how AMPK?2 activation regulates the expression and activity of MMP2 and their inhibitors, TIMPs, in VSMC and macrophages, two major cell types in the aneurismal vessels. Proposed studies on the link between cigarette smoke, MMPs and aneurysm pathogenesis are highly significant, as the achievement of its goals will directly lead to a better understanding of the fundamental pathologic mechanisms that contribute to the progression of aneurismal degeneration by smoking and other risk factors, and most importantly, could provide specific possibilities for therapeutic approaches.
Abdominal aortic aneurysm (AAAs) is the most common form of aortic aneurysm and uncontrolled growth of AAAs frequently leads to rupture resulting in approximately 80% mortality. Epidemical studies suggest that cigarette smoke increases the risk of AAAs 7.6-fold and smoking is the only modifiable factor associated with the development, expansion, and rupture of AAAs. In this application, a combination of pharmacological, molecular, and genetic means with gain-of-function and loss-of-function approaches will be used to establish a causative link between cigarette smoke and AAAs in animals in vivo. The completion of this project will increase our understanding of the fundamental pathologic mechanisms that contribute to the progression of aneurismal degeneration by smoking and other risk factors, and most importantly, could provide specific possibilities for therapeutic approaches.
|Song, Ping; Zou, Ming-Hui (2014) Redox regulation of endothelial cell fate. Cell Mol Life Sci 71:3219-39|
|Li, Hongliang; Min, Qing; Ouyang, Changhan et al. (2014) AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response. Biochim Biophys Acta 1842:1844-54|
|Zhang, Wencheng; Wang, Qilong; Wu, Yue et al. (2014) Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo. Circulation 129:1428-39|
|Okon, Imoh S; Coughlan, Kathleen A; Zou, Ming-Hui (2014) Liver kinase B1 expression promotes phosphatase activity and abrogation of receptor tyrosine kinase phosphorylation in human cancer cells. J Biol Chem 289:1639-48|
|Shirwany, Najeeb A; Zou, Ming-Hui (2014) AMPK: a cellular metabolic and redox sensor. A minireview. Front Biosci (Landmark Ed) 19:447-74|
|Li, Hongliang; Lee, Jiyeon; He, Chaoyong et al. (2014) Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids. Am J Physiol Endocrinol Metab 306:E197-209|
|Zhu, Huaiping; Foretz, Marc; Xie, Zhonglin et al. (2014) PRKAA1/AMPK?1 is required for autophagy-dependent mitochondrial clearance during erythrocyte maturation. Autophagy 10:1522-34|
|Wang, Qiongxin; Zhang, Miao; Ding, Ye et al. (2014) Activation of NAD(P)H oxidase by tryptophan-derived 3-hydroxykynurenine accelerates endothelial apoptosis and dysfunction in vivo. Circ Res 114:480-92|
|Okon, Imoh S; Coughlan, Kathleen A; Zhang, Cheng et al. (2014) Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis. J Clin Invest 124:4590-602|
|He, Chaoyong; Zhu, Huaiping; Li, Hongliang et al. (2013) Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes 62:1270-81|
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