AIP1 Prevents Graft Arteriosclerosis by Inhibiting Interferon-γ–Dependent Smooth Muscle Cell Proliferation and Intimal Expansion

Yu, Luyang; Qin, Lingfeng; Zhang, Haifeng; He, Yun; Chen, Hong; Pober, Jordan S.; Tellides, George; Wang, Min

doi:10.1161/circresaha.111.248245

Cited by 53 publications

(67 citation statements)

References 45 publications

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“…Although grafting between fully mismatched strains results in intense inflammation and loss of medial VSMCs within 2 weeks, grafting between single minor histocompatibility antigen mismatched strains leads to sparing of medial infiltration and survival of medial VCMCs greater than 2 to 4 weeks. 68,69 These studies reinforce the concept for an immunoregulatory environment created by the intrinsic cells of the arterial media or the ECM that they produce.…”

Section: Concept Of Medial Immunoprivilegesupporting

confidence: 60%

Inflammatory and Immune Responses in the Arterial Media

Tellides

Pober

2015

Circulation Research

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Inflammatory arterial diseases differentially affect the compartments of the vessel wall. The intima and adventitia are commonly involved by the disease process, with luminal and microvascular endothelial cells playing a critical role in the recruitment and activation of leukocytes. In contrast, the avascular media is often spared by immune-mediated disorders. Surprisingly, vascular smooth muscle cells (VSMCs), the predominant and often exclusive cell type of the media, are capable of robust proinflammatory responses to diverse stressors. The multiple cytokines and chemokines produced within the media can profoundly affect macrophage and T cell function, thus amplifying and shaping innate and adaptive immune responses. On the other hand, VSMCs and the extracellular matrix that they produce also display significant anti-inflammatory properties. The balance between the pro- and anti-inflammatory effects of VSMCs and their extracellular matrix versus the strength of the inciting immunologic events determines the pattern of medial pathology. Limitations on the extent of medial infiltration and injury, defined as medial immunoprivilege, are typically seen in arteriosclerotic diseases, such as atherosclerosis and transplant vasculopathy. Conversely, breakdown of medial immunoprivilege that manifests as more intense leukocytic infiltrates, loss of VSMCs, and destruction of the extracellular matrix architecture is a general feature of certain aneurysmal diseases and vasculitides. In this review, we consider the inflammatory and immune functions of VSMCs and how they may lead to medial immunoprivilege or medial inflammation in arterial diseases.

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Section: Concept Of Medial Immunoprivilegesupporting

confidence: 60%

Inflammatory and Immune Responses in the Arterial Media

Tellides

Pober

2015

Circulation Research

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“…32 DAB2IP was shown to limit JAK-dependent STAT1/3 and PI3K-Akt activation by interferon gamma (Figure 4e), reducing proliferation and migration of vascular smooth muscle cells during neo-intima formation. 33,34 In non-muscle invasive bladder cancer, DAB2IP-dependent inhibition of STAT3 has been reported to limit expression of Twist1 and P-glycoprotein, crucial factors for chemoresistance. 35 In prostate cancer cells, DAB2IP was found to directly bind STAT3, suppressing transactivation and expression of the anti-apoptotic target survivin.…”

Section: Ask1-jnkmentioning

confidence: 99%

“…Indeed, DAB2IP − / − mice show enhanced inflammation in models of ischemic hind limb, graft arteriosclerosis, and inflammatory angiogenesis. 4,33,34,54 In hyperlipidemic ApoE − / − mice, DAB2IP KO increases secretion of inflammatory cytokines and augments macrophage infiltration, thereby inducing endothelial dysfunction and early phases of atherosclerosis. 54 Notably, vascular endothelial-specific depletion of DAB2IP promotes tumor growth and dissemination in melanoma and breast cancer mouse models, favoring establishment of a prometastatic microenvironment.…”

Section: Dab2ip Inactivation Fosters Tumor Progressionmentioning

confidence: 99%

“…2,18,34,55 For instance, TNFα induces invasion in DAB2IP-inactivated breast cancer cells, triggering upregulation of a subset of NF-κB and ASK1/JNK target genes enriched in matrix-remodeling enzymes and chemokines. Intriguingly, such response can also recruit cytotoxic immune cells, potentially affecting tumor progression and prognosis.…”

Section: Dab2ip Inactivation Fosters Tumor Progressionmentioning

confidence: 99%

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Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

2016

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One of the most defining features of cancer is aberrant cell communication; therefore, a molecular understanding of the intricate network established among tumor cells and their microenvironment could significantly improve comprehension and clinical management of cancer. The tumor suppressor DAB2IP (Disabled homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), has an important role in this context, as it modulates signal transduction by multiple inflammatory cytokines and growth factors. DAB2IP is a Ras-GAP, and negatively controls Ras-dependent mitogenic signals. In addition, acting as a signaling adaptor, DAB2IP modulates other key oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptors. Therefore, DAB2IP inactivation can provide a selective advantage to tumors initiated by a variety of driver mutations. In line with this role, DAB2IP expression is frequently impaired by methylation in cancer. Interestingly, recent studies reveal that tumor cells can employ other sophisticated mechanisms to disable DAB2IP at the post-transcriptional level. We review the mechanisms and consequences of DAB2IP inactivation in cancer, with the purpose to support and improve research aimed to counteract such mechanisms. We suggest that DAB2IP reactivation in cancer cells could be a strategy to coordinately dampen multiple oncogenic pathways, potentially limiting progression of a wide spectrum of tumors.

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“…Consequently, the subsequent changes seen in the interposed vessel segment are solely a response of host cells that have repopulated the decellularized vessel scaffold, creating a highly artifactual situation of limited relevance as a model for the changes in graft vessels that occur in the clinic. We have recently developed two new mouse models to circumvent these problems 21 . The first model involves interposition of a vessel segment from a male mouse into a female recipient of the same inbred strain (C57BL/6J).…”

Section: Introductionmentioning

confidence: 99%

Mouse Models for Graft Arteriosclerosis

Qin

Wang

2013

JoVE

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Graft arteriosclerois (GA), also called allograft vasculopathy, is a pathologic lesion that develops over months to years in transplanted organs characterized by diffuse, circumferential stenosis of the entire graft vascular tree. The most critical component of GA pathogenesis is the proliferation of smooth muscle-like cells within the intima. When a human coronary artery segment is interposed into the infra-renal aortae of immunodeficient mice, the intimas could be expand in response to adoptively transferred human T cells allogeneic to the artery donor or exogenous human IFN-γ in the absence of human T cells. Interposition of a mouse aorta from one strain into another mouse strain recipient is limited as a model for chronic rejection in humans because the acute cell-mediated rejection response in this mouse model completely eliminates all donor-derived vascular cells from the graft within two-three weeks. We have recently developed two new mouse models to circumvent these problems. The first model involves interposition of a vessel segment from a male mouse into a female recipient of the same inbred strain (C57BL/6J). Graft rejection in this case is directed only against minor histocompatibility antigens encoded by the Y chromosome (present in the male but not the female) and the rejection response that ensues is sufficiently indolent to preserve donor-derived smooth muscle cells for several weeks. The second model involves interposing an artery segment from a wild type C57BL/6J mouse donor into a host mouse of the same strain and gender that lacks the receptor for IFN-γ followed by administration of mouse IFN-γ (delivered via infection of the mouse liver with an adenoviral vector. There is no rejection in this case as both donor and recipient mice are of the same strain and gender but donor smooth muscle cells proliferate in response to the cytokine while host-derived cells, lacking receptor for this cytokine, are unresponsive. By backcrossing additional genetic changes into the vessel donor, both models can be used to assess the effect of specific genes on GA progression. Here, we describe detailed protocols for our mouse GA models. Video LinkThe video component of this article can be found at

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AIP1 Prevents Graft Arteriosclerosis by Inhibiting Interferon-γ–Dependent Smooth Muscle Cell Proliferation and Intimal Expansion

Cited by 53 publications

References 45 publications

Inflammatory and Immune Responses in the Arterial Media

Inflammatory and Immune Responses in the Arterial Media

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

Mouse Models for Graft Arteriosclerosis

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