IFN-gamma, smooth muscle cells and graft arteriosclerosis

IFN-γ、平滑肌细胞与移植物动脉硬化

• 批准号: 7297623
• 负责人: George Tellides
• 金额: $ 48.45万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7297623
• 关键词: SCID mouse; acute phase protein; animal tissue; apoptosis; arteriosclerosis; biological models; blood vessel transplantation; cell proliferation; coronary artery; delayed hypersensitivity; human subject; immunoregulation; inflammation; inhibitor /antagonist; interferon gamma; laboratory mouse; ligands; mTOR protein; nucleic acids; organ culture; peroxisome proliferator activated receptor; platelet derived growth factor; protein kinase; transcription factor; transplant rejection; vascular smooth muscle; xenotransplantation

Chronic rejection, the major limitation of cardiac transplantation, is characterized by pathological remodeling and dysfunction of coronary arteries, termed graft arteriosclerosis (GA). The pathogenesis of GA is poorly understood, but is likely immune-mediated and may result from chronic delayed-type hypersensitivity responses by recipient T cells to donor vascular antigens through the secretion of cytokines, such as interferon-gamma (IFN-gamma). Paradoxically, IFN-gamma is generally thought to have an antiproliferative effect on vascular smooth muscle cells (VSMCs) and was considered to function as a proarteriosclerotic agent solely because of its immunomodulatory effects on endothelial cells and infiltrating leukocytes. However, we have found that IFN-gamma elicits arteriosclerosis in the absence of leukocytes. Our prior observations and current preliminary studies have led us to hypothesize that IFN-gamma induces VSMC proliferation that depends on a mTOR/p70S6K pathway, sensitizes VSMCs to apoptosis through upregulation of XAF1 and Noxa, and primes VSMCs for innate immune responses to fragmented nucleic acids by induction of RIG-I and MDA5. These disparate effects of IFN-gamma on VSMC survival and inflammation interact and cause intimal expansion, outward vascular remodeling, and vasodysfunction of conduit coronary arteries which ultimately determine lumen size and blood flow. We further hypothesize that these direct actions of IFN-gamma on VSMCs will be inhibited by peroxisome proliferator-activated receptor (PPAR)gamma ligands. To test our hypotheses with the experiments planned in this project, we have formed productive collaborations with other investigators of the program application and together we have developed novel models of GA in which human coronary arteries are interposed in severely immunodeficient mouse hosts that produce human IFN-gamma by adenoviral vector infection. Our methods are supplemented by mouse artery transplantation models and by cellular and molecular studies of human VSMCs. We will use these approaches to elucidate the effects of IFN-gamma on arterial tissue in vivo and in vitro. The outcomes of these studies will provide considerable new information about the role of IFN-gamma in GA, may identify novel therapeutic targets to treat and image GA, and investigate mechanisms of inhibiting GA by existing pharmacological agents.

慢性排斥反应是心脏移植的主要限制因素，其特征是病理性重构 和冠状动脉功能障碍，称为移植物动脉硬化（GA）。GA的发病机制不明确， 可以理解，但可能是免疫介导的，可能由慢性迟发型超敏反应引起 受体T细胞通过分泌细胞因子对供体血管抗原的应答，例如 干扰素-γ（IFN-γ）。有趣的是，IFN-γ通常被认为对血管平滑肌细胞（VSMC）具有抗增殖作用，并且被认为仅作为促动脉炎剂起作用，因为 其对内皮细胞和浸润性白细胞的免疫调节作用。然而，我们发现， IFN-γ在缺乏白细胞的情况下诱发动脉硬化。我们先前的观察和目前的初步 研究使我们假设IFN-γ诱导VSMC增殖依赖于mTOR/p70 S6 K 途径，通过上调XAF 1和Noxa使VSMCs对凋亡敏感，并使VSMCs 通过诱导RIG-I和MDA 5对片段化核酸的先天免疫应答。这些不同 IFN-γ对VSMC存活和炎症的影响相互作用，导致内膜扩张，向外血管扩张， 最终决定管腔大小的导管冠状动脉的重塑和血管功能障碍， 血流我们进一步假设IFN-γ对VSMCs的这些直接作用将被抑制， 过氧化物酶体增殖物激活受体（PPAR）γ配体。为了验证我们的假设 计划在这个项目中，我们已经形成了富有成效的合作与其他研究人员的计划 应用，我们一起开发了新的遗传算法模型，其中人类冠状动脉是 通过腺病毒载体插入严重免疫缺陷小鼠宿主中产生人IFN-γ 感染我们的方法是补充小鼠动脉移植模型和细胞和 人类VSMC的分子研究。我们将使用这些方法来阐明IFN-γ对 动脉组织在体内和体外。这些研究的结果将提供相当多的新信息 关于IFN-γ在GA中的作用，可以确定新的治疗靶点来治疗和成像GA，并研究 通过现有的药理学试剂抑制GA的机制。