Inactivation of PI3Kδ Induces Vascular Injury and Promotes Aneurysm Development by Upregulating the AP-1/MMP-12 Pathway in Macrophages

Abstract

A neurysms frequently lead to high morbidity and mortality as a result of rupture or dissection without symptoms. 1 Aortic aneurysms, including abdominal aortic aneurysm (AAA), thoracic aneurysms, and carotid aneurysms, are highly common conditions, with AAA being 3 times more prevalent than thoracic aneurysm.2 Although they are typically regarded as being distinct entities, vascular inflammation is a common pathogenic factor in them. 3,4 Pathological features of aneurismal diseases include transmural inflammatory cell infiltration, noticeable breakdown of elastic lamellae, smooth muscle cell loss, endothelial cell death and detachment, neovascularization, calcium deposition, and focal aneurysmal dilation of the vessel wall. 5,6 However, the specific cellular mechanisms that underlie aneurysm formation and progression are poorly understood.Increasing evidence 7,8 points to an important role for innate immune cells in the pathobiology of aneurysms. Monocytes/ macrophages infiltrate the vessel wall and release proteases, including elastase (matrix metalloproteinase-12 ) and metalloproteinases that compromise the integrity of the vascular wall through degradation of the extracellular matrix (ECM). Monocytes/macrophages also secrete inflammatory cytokines in the media and adventitia of aneurysmatic vessels, such as tumor necrosis factor (TNF)-α, interferon-γ, © 2014 American Heart Association, Inc. 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 ...

Gingival Tissue Inflammation Promotes Increased Matrix Metalloproteinase-12 Production by CD200Rlow Monocyte-Derived Cells in Periodontitis

“…The CD200R can inhibit the Ras signaling network (57), a signaling pathway that is activated, for example, by CSF2 and TLR ligation (58). The PI3K, downstream of Ras, induces Activator protein-1, which is part of a proinflammatory pathway inducing MMP12 expression (59,60). Although there are no previous reports on CD200R expression in PD, reduced CD200R expression has been associated with rheumatoid arthritis (61), a disease associated with increased levels of MMP12 (24).…”

Aortic Aneurysms

“…Genetic inactivation of p110δ in mice led to accumulation of macrophages in the aorta and augmented calcium chloride-induced AAA. 69 …”

Phosphoinositide 3-Kinase (PI3K) Subunit p110δ Is Essential for Trophoblast Cell Differentiation and Placental Development in Mouse

“…In our previous work, MMP-12 was found to be up-regulated in arteries of p110δ D910A/D910A mice, leading to the degradation of extracellular matrix in the vessels36. Consequently, we evaluated the expressions of MMP-12 and MMP-2 in placenta of p110δ WT and p110δ D910A/D910A female mice, respectively (Fig.…”

“…Originally identified through p110δ role in immune responses 31 , p110δ has been demonstrated via gene targeting studies in mice to be essential in maintaining the function of immunocytes and disrupted PI3K p110δ signaling dysregulates maternal immune cells and increases fetal mortality in mice 32 33 34 35 . Our group reported recently that p110δ also plays an essential role in physiological vascular regulation through regulating AP-1/MMP-12 pathway in mice 36 . Quite serendipitously, we discovered the litter size is significantly reduced during breeding of p110δ mutant inactive mice (p110δ D910A/D910A ) as compared with that of the wild-type (p110δ WT ).…”