| First Author | Zheng L | Year | 2015 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 35 |
| Issue | 2 | Pages | 368-77 |
| PubMed ID | 25503990 | Mgi Jnum | J:240906 |
| Mgi Id | MGI:5896711 | Doi | 10.1161/ATVBAHA.114.304365 |
| Citation | Zheng L, et al. (2015) Inactivation of PI3Kdelta induces vascular injury and promotes aneurysm development by upregulating the AP-1/MMP-12 pathway in macrophages. Arterioscler Thromb Vasc Biol 35(2):368-77 |
| abstractText | OBJECTIVE: An aneurysm is an inflammatory vascular condition. Phosphatidylinositol 3-kinases delta is highly expressed in leukocytes, and play a key role in innate immunity. However, the link between phosphatidylinositol 3-kinases delta and aneurysm development has not yet been elucidated. APPROACH AND RESULTS: Carotid ligation unexpectedly induced characteristic aneurysm formation beneath the ligation point in p110delta(D910A/D910A) mice (n=25; P<0.001 versus wild-type). Besides, p110delta 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 p110delta(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 p110delta(D910A/D910A) mice (n=10; P<0.01 versus wild-type). In vitro, p110delta inactivation marked increase peritoneal macrophages recruitment and synergistically enhance tumor necrosis factor-alpha-induced recruitment. A specific phosphatidylinositol 3-kinases delta inhibitor (IC87114) or genetic p110delta 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-alpha on activator protein-1-binding activity (n=5; P<0.01 versus tumor necrosis factor-alpha treatment groups). Knockdown of c-Jun suppressed the effect of the IC87114 and tumor necrosis factor-alpha on MMP-12 mRNA expression (n=5 in each group; P<0.01 versus scrRNA treatment groups). CONCLUSIONS: Our findings demonstrate that p110delta 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. |
