Novel mechanisms of age-enhanced vasculopathy after heart transplantation

项目总结

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.