title: Inhibition of endoplasmic reticulum stress signaling pathway: A new mechanism of statins to suppress the development of abdominal aortic aneurysm.
abstract: BACKGROUND
  Abdominal aortic aneurysm (AAA) is a potentially lethal disease with extremely poor survival rates once the aneurysm ruptures. Statins may exert beneficial effects on the progression of AAA. However, the underlying mechanism is still not known. The purpose of the present study is to investigate whether statin could inhibit AAA formation by inhibiting the endoplasmic reticulum (ER) stress signal pathway.
  
  
  METHODS
  A clinically relevant AAA model was induced in Apolipoprotein E-deficient (ApoE-/-) mice, which were infused with angiotensin II (Ang II) for 28 days. These mice were randomly divided into following 4 groups: saline infusion alone; Ang II infusion alone; Ang II infusion plus Atorvastatin (20mg/kg/d); and Ang II infusion plus Atorvastatin (30mg/kg/d). Besides, another AAA model was induced in C57 mice with extraluminal CaCl2, which were divided into 3 groups: sham group, CaCl2-induced AAA group, and CaCl2-induced AAA plus atorvastatin (20mg/kg/d) group. Then, aortic tissue was excised for further examinations, respectively. In vitro studies, Ang II with or without simvastatin treatment were applied to the vascular smooth muscle cells (VSMCS) and Raw 264.7 cells. The ER stress signal pathway, apoptosis and inflammatory response were evaluated by in vivo and in vitro assays.
  
  
  RESULTS
  We found that higher dose of atorvastatin can effectively suppress the development and progression of AAA induced by Ang II or CaCl2. Mechanistically, the activation of ER stress and inflammatory response were found involved in Ang II-induced AAA formation. The atorvastatin infusion significantly reduced ER stress signaling proteins, the number of apoptotic cells, and the activation of Caspase12 and Bax in the Ang II-induced ApoE-/- mice, compared with mice treated by Ang II alone. Furthermore, proinflammatory cytokines such as IL-6, IL-8, IL-1β were all remarkably inhibited after atorvastatin treatment. In vitro, the inhibitory effect of simvastatin on the ER stress signal pathway could be observed in both vascular smooth muscle cells and macrophages, and these inhibitory effects of statin were in a dose-dependent manner. In addition, apoptosis was induced with Ang II treatment. The maximal inhibitory effect of simvastatin on apoptosis was observed at 10 μmol/l.
  
  
  CONCLUSIONS
  We conclude that higher dose of statin can effectively suppress the development of AAA, and reduce ER stress, ER stress-associated apoptosis signaling pathways, and inflammatory response. These findings reveal a new mechanism underlying the inhibitory effect of statin on AAA formation/progression.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Gangsheng
authors.initials: G
authors.lastname: Lu
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dating
authors.initials: D
authors.lastname: Sun
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Houjuan
authors.initials: H
authors.lastname: Zuo
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Yan
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000069059:Atorvastatin / Q000494:pharmacology*; D002122:Calcium Chloride; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000804:Angiotensin II; D000069059:Atorvastatin; D002122:Calcium Chloride