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. 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 CaCl 2 -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.