To Study the Effects and Underlying Mechanisms of B Type Natriuretic Peptide in Endothelial-Mesenchymal Transition: a Study Regarding to Cardiac Allograft Vasculopathy

Theoretical basis Heart transplantation is the main method to surmount the end-stage heart failure. However, when the donor heart is transplanted into recipient, the immunity will active and begins to resist the donor heart; this process is known as rejection, and the mechanisms are complicated. Chronic reject will induce the occurrence of cardiac allograft vasculopathy (CAV) which resulting in failure of donor heart. At present, the evidences have only demonstrated that one of the main causes of CAV is endothelial-mesenchymal transition (endoMT). Additionally, the increasing of plasma B type natriuretic peptide (BNP) and thrombomodulin (TM) are observed in CAV patients. BNP and TM had been suggested to be indicators of chronic rejection. However, whether elevated BNP regulates the development of CAV mediating by endoMT, and TM is also involved are unknown. Therefore, we propose the hypothesis that BNP may decrease the expression of TM in endothelial progenitor cells (EPCs), and thus decrease the function of EPCs and increase the endoMT which resulting in the CAV. The project is expected in three years to complete the following goals Analysis of clinical specimens: During the implementation of this project (from Aug-01-2017 to Jul-31-2020), 18-30 patients who undergo heart transplantation will be included. We will analysis the circulating EPCs and SMPCs level, serum level of BNP and TM, and collect clinical pathological data from biopsy in several time points (before transplantation, post-transplantation for 1, 3, 6, 9, and 12 months). Analyze the correlation between the clinical situation of rejection and levels of EPCs, SMPCs, BNP, and TM. Animal study: We plan to perform animal study in the first and second years. The model of PVG rat abdominal aorta graft to ACI rat abdominal aorta will be used to explore the effects of administrated-BNP in post-transplantation vasculopathy. The plasma level of TM and BNP will be analyzed. Additionally, the rats will be sacrificed at the 90th day after the surgery and the donor aorta will be removed. To observe the intimal hyperplasia and endoMT-related proteins expression on rat aorta. In vitro study: We plan to perform in vitro study in the second and third years. To investigate the effects of BNP on EPCs function (migration, cell adhesion, senescence, and apoptosis, etc) and EndoMT. Additionally, we also explore the possible role of TM in the process. Expected influence on social, economic and academic development The chronic rejection-induced CAV may lead to the loss of donor heart function. Even thought the underlying mechanisms are complicated, scientists still need to be categorized to explore the truth, and in future it will have the means to prolong the life and usage of donor heart in clinic. Therefore, this research project is proposed in this legislation. We plan to elucidate the biological properties of endothelial progenitor cells in adult, and to disclose the mechanisms and situations under which the cells are integrated into the vessel wall and function as normal. We speculate that the results will be far-reaching significances in theoretical and clinical value regarding to the prevention and treatment of CAV. BNP and TM may not only serve as an indicator of rejection severity in clinical patients after cardiac transplantation, but we also wish the exploration will provide insight into its roles and effects in donor heart. In the future, clinicians may through the regulation of TM and BNP expressions to extend the life and survival of donor heart.