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: 10329932
• 负责人: Daniel Robert Goldstein
• 金额: $ 49.66万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10329932
• 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; Parkin; 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; 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， 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， 由于供体年龄的增加，使用率正在下降。老年捐赠者的移植 年龄超过55岁通常被忽略，因为供体年龄的增加是最强的独立因素， 死亡率和慢性移植物血管病（CAV）的发展， 器官移植此外，老年供体心脏通常表现出动脉粥样硬化，使其不适合移植。 移植然而，供体年龄增加CAV的机制仍然未知。我们事先 一项研究表明，老年鼠血管平滑肌细胞（VSMC）有助于血管炎症 通过MyD 88产生IL-6、CCL 2和骨桥蛋白，MyD 88是一种先天性免疫适配蛋白， Toll样受体。我们的初步数据还表明，衰老损害线粒体自噬，即，清除 受损的线粒体，在VSMC内，以增强血管炎症。因此，我们假设， 老年供体VSMC内受损的线粒体自噬导致MyD 88依赖性血管炎症， Cav.为了验证这一假设，我们将使用在VSMC内选择性缺失MyD 88的新小鼠， 检查在鼠中老年供体血管系统的VSMC内MyD 88表达是否对CAV至关重要。 心脏移植模型（目的1）。我们还将检测老年人VSMC中MyD 88的表达是否与年龄相关。 供体血管系统对于心脏移植后预先存在的供体动脉粥样硬化的进展至关重要。 通过采用一种新的方法在供体心脏中诱导动脉粥样硬化， 移植此外，我们将使用年轻的小鼠，其中自噬或线粒体自噬被禁用， VSMC，以确定这些细胞中的自噬或线粒体自噬是否控制CAV（目的2）。我们将补充这一点 通过检查是否给予增强自噬的试剂，例如，雷帕霉素或线粒体自噬， 放线菌素可降低老年供体小鼠心脏移植后的CAV。我们希望我们的研究能直接 将供体脉管系统中的炎症途径与CAV联系起来。我们的研究结果可能会导致新的治疗方法， 减少CAV的发展和供体心脏中天然血管动脉粥样硬化的进展。 这种疗法可以大大增加心脏移植供体的数量，挽救患者的生命。 心脏衰竭晚期

项目成果

Inactivation of Interleukin-4 Receptor α Signaling in Myeloid Cells Protects Mice From Angiotensin II/High Salt-Induced Cardiovascular Dysfunction Through Suppression of Fibrotic Remodeling.

• DOI: 10.1161/jaha.120.017329
• 发表时间: 2021-07-06
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Song J;Frieler RA;Vigil TM;Ma J;Brombacher F;Goonewardena SN;Goldstein DR;Mortensen RM
• 通讯作者: Mortensen RM

Immune mechanisms of cardiac aging.

心脏衰老的免疫机制。

• DOI: 10.20517/jca.2023.02
• 发表时间: 2023
• 期刊: The journal of cardiovascular aging
• 作者: Goldstein,DanielR;Abdel-Latif,Ahmed
• 通讯作者: Abdel-Latif,Ahmed

Innovations in cardiac transplantation.

心脏移植的创新。

• DOI: 10.1097/hco.0000000000000392
• 发表时间: 2017
• 期刊: Current opinion in cardiology
• 影响因子: 2.3
• 作者: Hasan,Reema;Ela,AshrafAbouEl;Goldstein,Daniel
• 通讯作者: Goldstein,Daniel

Treating exuberant, non-resolving inflammation in the lung; Implications for acute respiratory distress syndrome and COVID-19.

• DOI: 10.1016/j.pharmthera.2020.107745
• 发表时间: 2021-05
• 期刊: Pharmacology & therapeutics
• 影响因子: 13.5
• 作者: Gilroy DW;De Maeyer RPH;Tepper M;O'Brien A;Uddin M;Chen J;Goldstein DR;Akbar AN
• 通讯作者: Akbar AN

Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis.

与年龄相关的脂肪组织炎症促进单核细胞趋化性并增强动脉粥样硬化。

• DOI: 10.1111/acel.13783
• 发表时间: 2023-02
• 期刊: Aging cell
• 影响因子: 7.8