Novel mechanisms of age-enhanced vasculopathy after heart transplantation

心脏移植后年龄加重血管病变的新机制

• 批准号: 10088381
• 负责人: Daniel Robert Goldstein
• 金额: $ 54.31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-05 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088381
• 关键词: Adaptor Signaling Protein; Address; Age; Age-Years; Aging; Allografting; Atherosclerosis; Autophagocytosis; CCL2 gene; Cells; Chronic; Clinical Research; Complement; Data; Development; Disabled Persons; Donor person; Effectiveness; Exhibits; Genes; Heart; Heart Transplantation; Heart failure; Hyperlipidemia; Immune; Immune signaling; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; Lead; Link; Methods; Mitochondria; Mus; Organ Transplantation; Pathway interactions; Patients; Publishing; Reporter; Risk Factors; Role; Sirolimus; Smooth Muscle Myocytes; Testing; Therapeutic; Toll-like receptors; Transplantation; Vascular Diseases; Vascular Smooth Muscle; Work; age effect; aged; allotransplant; atherogenesis; cell age; insight; monocyte; mortality; novel; novel strategies; novel therapeutics; osteopontin; parkin gene/protein; recruit; transplant model; vascular inflammation

Project Summary Heart transplantation is a vital therapy for end-stage heart failure. The effectiveness of this therapy, however, is largely limited by the shortage of donors. Regrettably, less than 40% of available heart donations are used for transplantation and the rate of use is declining due to increasing donor age. Transplants from donors older than 55 years of age are typically disregarded as increasing donor age is the strongest independent factor for both mortality and the development of chronic allograft vasculopathy (CAV), the leading cause of graft loss for organ transplants. Additionally, older donor hearts often exhibit atherosclerosis, rendering them unsuitable for transplantation. However, the mechanisms by which donor age increases CAV remain unknown. Our prior work demonstrates that aged murine vascular smooth muscle cells (VSMC) contribute to vascular inflammation by producing IL-6, CCL2 and osteopontin via MyD88, an innate immune adaptor protein downstream of the Toll like receptors. Our preliminary data also indicate that aging impairs mitophagy, i.e., the clearance of damaged mitochondria, within VSMC to enhance vascular inflammation. We therefore hypothesize that impaired mitophagy within aged donor VSMC leads to MyD88-dependent vascular inflammation that enhances CAV. To test this hypothesis, we will use novel mice in which MyD88 is selectively deleted within VSMC to examine whether MyD88 expression within VSMC of the aged donor vasculature is critical for CAV in a murine heart transplant model (Aim 1). We will also examine whether MyD88 expression within VSMC of the aged donor vasculature is critical for the progression of pre-existing donor atherosclerosis after cardiac transplantation by employing a novel method to induce atherosclerosis in the donor heart prior to transplantation. In addition, we will use young mice in which either autophagy or mitophagy is disabled within VSMC, to determine if autophagy or mitophagy in these cells controls CAV (Aim 2). We will complement this approach by examining if administration of agents that enhance autophagy, e.g., rapamycin or mitophagy e.g., actinonin, to aged donor mice reduces CAV after cardiac transplantation. We expect that our study will directly link inflammatory pathways in the donor vasculature to CAV. Our results could lead to new therapeutics to reduce both the development of CAV and the progression of native vessel atherosclerosis in donor hearts. Such therapeutics could tremendously increase the pool of heart transplant donors and save lives of patients with end stage heart failure.

项目摘要 心脏移植是治疗终末期心力衰竭的重要手段。然而，这种疗法的有效性， 在很大程度上受到捐助者短缺的限制。令人遗憾的是，只有不到40%的可用心脏捐赠被使用 由于供者年龄的增加，使用率正在下降。来自年长捐赠者的移植 55岁以上的人通常被忽略，因为增加供者的年龄是影响 慢性移植物血管病(CAV)的死亡率和发展，是移植物丢失的主要原因 器官移植。此外，较年长的供者心脏通常表现为动脉粥样硬化，使其不适合于 移植。然而，供者年龄增加CAV的机制仍不清楚。我们的前辈 研究表明，衰老的小鼠血管平滑肌细胞(VSMC)有助于血管炎症 通过MyD88产生IL-6、CCL2和骨桥蛋白，MyD88是一种天然免疫适配器蛋白，位于 Toll样受体。我们的初步数据还表明，衰老会损害有丝分裂，即清除 VSMC内的线粒体受损，以加强血管炎症。因此，我们假设 老年供者VSMC内丝裂原吞噬功能受损导致MyD88依赖性血管炎症 卡夫。为了验证这一假设，我们将使用新型小鼠，其中MyD88在VSMC内选择性缺失，以 检测老年供体血管VSMC中MyD88的表达是否对小鼠CAV至关重要 心脏移植模型(目标1)。我们还将检测MyD88在老年人VSMC中的表达 供体血管是心脏术后原有供体动脉粥样硬化进展的关键 采用一种新方法在供心移植前诱导动脉粥样硬化 移植。此外，我们将使用体内自噬或有丝分裂吞噬功能被禁用的幼鼠 VSMC，以确定这些细胞中的自噬或有丝分裂吞噬是否控制CAV(目标2)。我们将补充这一点 通过检查是否给予增强自噬的药物，例如雷帕霉素或有丝分裂吞噬， 老年供体小鼠应用放线宁可降低心脏移植后CAV。我们预计我们的研究将直接 将供体血管中的炎症途径与CAV联系起来。我们的结果可能会导致新的治疗方法 减少CAV的发展和供体心脏天然血管动脉粥样硬化的进展。 这种疗法可以极大地增加心脏移植捐赠者的数量，挽救患者的生命。 伴有终末期心力衰竭。