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Inactivation of PI3Kδ induces vascular injury and promotes aneurysm development by upregulating the AP-1/MMP-12 pathway in macrophages.
Zheng, Lingyun; Xing, Liying; Zeng, Cuiling; Wu, Teng; Gui, Yali; Li, Weidong; Lan, Tian; Yang, Yongxia; Gu, Quliang; Qi, Cuiling; Zhang, Qianqian; Tang, Futian; He, Xiaodong; Wang, Lijing.
Afiliação
  • Zheng L; 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.
  • Xing L; 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.
  • Zeng C; 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.
  • Wu T; 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.
  • Gui Y; 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.
  • Li W; 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.
  • Lan T; 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.
  • Yang Y; 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.
  • Gu Q; 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.
  • Qi C; 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.
  • Zhang Q; 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.
  • Tang F; 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.
  • He X; 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.
  • Wang L; 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.
Arterioscler Thromb Vasc Biol ; 35(2): 368-77, 2015 Feb.
Article em En | MEDLINE | ID: mdl-25503990
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. APPROACH AND 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.
Assuntos
Aorta Abdominal/enzimologia; Aneurisma da Aorta Abdominal/enzimologia; Lesões das Artérias Carótidas/enzimologia; Artéria Carótida Primitiva/enzimologia; Macrófagos Peritoneais/enzimologia; Metaloproteinase 12 da Matriz/metabolismo; Fosfatidilinositol 3-Quinases/deficiência; Fator de Transcrição AP-1/metabolismo; Adenina/análogos & derivados; Adenina/farmacologia; Animais; Aorta Abdominal/efeitos dos fármacos; Aorta Abdominal/patologia; Aorta Abdominal/cirurgia; Aneurisma da Aorta Abdominal/induzido quimicamente; Aneurisma da Aorta Abdominal/genética; Aneurisma da Aorta Abdominal/patologia; Cloreto de Cálcio; Lesões das Artérias Carótidas/genética; Lesões das Artérias Carótidas/patologia; Artéria Carótida Primitiva/efeitos dos fármacos; Artéria Carótida Primitiva/patologia; Artéria Carótida Primitiva/cirurgia; Linhagem Celular; Classe I de Fosfatidilinositol 3-Quinases; Modelos Animais de Doenças; Ativação Enzimática; Proteínas da Matriz Extracelular/genética; Proteínas da Matriz Extracelular/metabolismo; Regulação Enzimológica da Expressão Gênica; Ligadura; Macrófagos Peritoneais/efeitos dos fármacos; Macrófagos Peritoneais/patologia; Masculino; Camundongos Endogâmicos C57BL; Camundongos Knockout; Fosfatidilinositol 3-Quinases/genética; Inibidores de Fosfoinositídeo-3 Quinase; Inibidores de Proteínas Quinases/farmacologia; Quinazolinas/farmacologia; Interferência de RNA; Transdução de Sinais; Fator de Transcrição AP-1/genética; Transfecção; Fator de Necrose Tumoral alfa/farmacologia
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aorta Abdominal / Artéria Carótida Primitiva / Aneurisma da Aorta Abdominal / Macrófagos Peritoneais / Fator de Transcrição AP-1 / Fosfatidilinositol 3-Quinases / Lesões das Artérias Carótidas / Metaloproteinase 12 da Matriz Tipo de estudo: Prognostic_studies Idioma: En Revista: Arterioscler Thromb Vasc Biol Ano de publicação: 2015 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aorta Abdominal / Artéria Carótida Primitiva / Aneurisma da Aorta Abdominal / Macrófagos Peritoneais / Fator de Transcrição AP-1 / Fosfatidilinositol 3-Quinases / Lesões das Artérias Carótidas / Metaloproteinase 12 da Matriz Tipo de estudo: Prognostic_studies Idioma: En Revista: Arterioscler Thromb Vasc Biol Ano de publicação: 2015 Tipo de documento: Article