title: Macrophage inflammasome mediates hyperhomocysteinemia-aggravated abdominal aortic aneurysm.
abstract: Abdominal aortic aneurysm (AAA) is a serious vascular disease with high mortality. Our previous study suggested that hyperhomocysteinemia (HHcy) exaggerates the occurrence of AAA. Here, we investigated whether macrophage inflammasome is involved in HHcy-aggravated AAA formation. Two independent HHcy-aggravated AAA models, perivascular calcium phosphate-treated C57BL/6 mice and angiotensin II (Ang II)-infused apolipoprotein E-deficient (ApoE(-/-)) mice were used. NLPR3, caspase 1, and interleukin-1β (IL-1β) levels were higher in aneurysmal lesions of both HHcy models compared to controls, preferentially in macrophages. Similarly, macrophage inflammasome activation was observed in vitro. Folic acid administration reversed the HHcy-accelerated AAA, with ameliorated activation of inflammasome in the tunica adventitia. Lentiviral silencing of NLRP3 significantly ameliorated HHcy-aggravated AAA formation. We observed increased mitochondrial production of reactive oxygen species (ROS) and energy switch from oxidative phosphorylation to glycolysis with excess Hcy in macrophages. Blocking mitochondrial ROS production in macrophages abolished inflammasome activation. Our study highlights the potential importance of macrophage inflammasome in the pathogenesis and development of HHcy-aggravated AAA.
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China.
authors: Weiliang
authors: W
authors: Sun
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China; Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, People's Republic of China.
authors: Yanli
authors: Y
authors: Pang
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China.
authors: Ziyi
authors: Z
authors: Liu
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China.
authors: Lulu
authors: L
authors: Sun
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China.
authors: Bo
authors: B
authors: Liu
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China.
authors: Mingjiang
authors: M
authors: Xu
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China.
authors: Yongqiang
authors: Y
authors: Dong
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China.
authors: Juan
authors: J
authors: Feng
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China.
authors: Changtao
authors: C
authors: Jiang
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China. Electronic address: kongw@bjmu.edu.cn.
authors: Wei
authors: W
authors: Kong
authors: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, People's Republic of China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China. Electronic address: xwang@bjmu.edu.cn.
authors: Xian
authors: X
authors: Wang
mesh_terms: D063194:Adventitia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002130:Calcium Phosphates / Q000009:adverse effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005492:Folic Acid / Q000494:pharmacology; D015870:Gene Expression; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D002130:Calcium Phosphates; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D005492:Folic Acid; C020243:calcium phosphate; D020170:Caspase 1
keywords: Abdominal aortic aneurysm; Hyperhomocysteinemia; Inflammasome; Macrophage; Mitochondrial reactive oxygen species