title: Inactivation of PI3Kδ induces vascular injury and promotes aneurysm development by upregulating the AP-1/MMP-12 pathway in macrophages.
abstract: OBJECTIVE
  An aneurysm is an inflammatory vascular condition. Phosphatidylinositol 3-kinases δ is highly expressed in leukocytes, and play a key role in innate immunity. However, the link between phosphatidylinositol 3-kinases δ and aneurysm development has not yet been elucidated.
  
  
  RESULTS
  Carotid ligation unexpectedly induced characteristic aneurysm formation beneath the ligation point in p110δ(D910A/D910A) mice (n=25; P<0.001 versus wild-type). Besides, p110δ inactivation exacerbated CaCl2-induced abdominal aortic aneurysms development. A reverse transcription polymerase chain reaction microarray revealed significant extracellular matrix components degradation and matrix metalloproteinases (MMPs) upregulation in the abdominal aorta of p110δ(D910A/D910A) mice. Similarly, the expression of both collagen I and IV was significantly decreased (n=10; P<0.05 versus wild-type) in carotid artery. Western blot assay confirmed that MMP-12 was significantly upregulated in arteries of p110δ(D910A/D910A) mice (n=10; P<0.01 versus wild-type). In vitro, p110δ inactivation marked increase peritoneal macrophages recruitment and synergistically enhance tumor necrosis factor-α-induced recruitment. A specific phosphatidylinositol 3-kinases δ inhibitor (IC87114) or genetic p110δ inactivation upregulated MMP-12 expression and c-Jun phosphorylation (n=6; P<0.05 versus wild-type macrophages). IC87114 also increased activator protein-1 DNA-binding activity (n=6; P<0.001 versus control) and enhanced the effect of tumor necrosis factor-α on activator protein-1-binding activity (n=5; P<0.01 versus tumor necrosis factor-α treatment groups). Knockdown of c-Jun suppressed the effect of the IC87114 and tumor necrosis factor-α on MMP-12 mRNA expression (n=5 in each group; P<0.01 versus scrRNA treatment groups).
  
  
  CONCLUSIONS
  Our findings demonstrate that p110δ inactivation leads to extracellular matrix degradation in vessels and promotes aneurysm development by inducing macrophages migration and upregulating the activator protein-1/MMP-12 pathway in macrophages.
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Zheng
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Liying
authors.initials: L
authors.lastname: Xing
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Cuiling
authors.initials: C
authors.lastname: Zeng
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Teng
authors.initials: T
authors.lastname: Wu
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Gui
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Li
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Tian
authors.initials: T
authors.lastname: Lan
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Yang
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Quliang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Cuiling
authors.initials: C
authors.lastname: Qi
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Futian
authors.initials: F
authors.lastname: Tang
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: He
authors.affiliation: From the Vascular Biology Research Institute (L.Z., L.X., C.Z., T.W., Y.G., W.L., T.L., Y.Y., Q.G., C.Q., Q.Z., F.T., X.H., L.W.) and Department of Basic Course (L.Z., Y.Y., Q.G.), Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China. wanglijing@gdpu.edu.cn.
authors.forename: Lijing
authors.initials: L
authors.lastname: Wang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002122:Calcium Chloride; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017536:Carotid Artery, Common / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D008026:Ligation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000225:Adenine; D002122:Calcium Chloride; D058534:Class I Phosphatidylinositol 3-Kinases; D016326:Extracellular Matrix Proteins; D053508:Matrix Metalloproteinase 12; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C477872:IC 87114; C421683:Pik3cd protein, mouse
keywords: activator protein-1; aneurysm; extracellular matrix; matrix metalloproteinases-12