INDUCIBLE NO SYNTHASE IN CARDIAC ALLOGRAFT REJECTION

心脏同种异体移植排斥反应中可诱导无合酶

• 批准号: 6537214
• 负责人: Paul J Cannon
• 金额: $ 31.99万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537214
• 关键词: BCL2 gene /protein; apoptosis; cardiac myocytes; eicosanoid metabolism; enzyme activity; enzyme induction /repression; enzyme inhibitors; enzyme mechanism; gene targeting; heart transplantation; homologous transplantation; inflammation; laboratory mouse; laboratory rat; necrosis; nitric oxide synthase; pentosyltransferase; prostaglandin endoperoxide synthase; prostaglandins; protease inhibitor; protein protein interaction; thromboxanes; transplant rejection; transport inhibitor

DESCRIPTION (adapted from the applicant's abstract): The general objective of the proposed research in this renewal application is to investigate the role of the inducible isoform of nitric oxide synthase (iNOS) in the biochemistry and pathobiology of cardiac allograft rejection. The central hypothesis to be tested is that NO produced by iNOS in macrophages infiltrating the myocardium and in the cardiac myocytes augments the myocardial inflammation and contributes to the death of cardiac myocytes. We have demonstrated: 1) that iNOS mRNA, protein, and enzyme activity are induced in endothelial cells, infiltrating macrophages and cardiomyocytes in rejecting cardiac allografts, and 2) that iNOS induction is accompanied by impaired ventricular function and death of heart muscle cells which occurs both by necrosis and by apoptosis. We now propose to investigate mechanisms responsible for necrosis, apoptosis, and iNOS expression during heart transplant rejection. Aim #1 is to investigate, using cultured cardiomyocytes and rat and mouse heterotopic cardiac transplantation models, the hypothesis that activation of polyadenosine 5' -diphosphoribose synthetase (PARS) by nitric oxide contributes to the necrosis of cardiac myocytes in vitro and during cardiac allograft rejection. Aim #2 is to investigate the hypothesis that myocardial inflammation, necrosis and apoptosis during cardiac allograft rejection are ameliorated using mice as allograft donors and recipients that are unable to express iNOS (iNOS-ko mice). Aim#3 is to investigate the hypotheses that apoptosis of cardiomyocytes triggered by NO can be inhibited by sem-selective iNOS inhibitors, by transfection with Bcl-2, and by administration of caspase inhibitors. Aim #4 is to investigate the interplay between iNOS and COX-2 in modulating prostaglandin and thromboxane synthesis during cardiac allograft rejection, the role of CD154-CD40 interaction in the expression of iNOS and COX-2 in cardiomyocytes and the effect of COX-2 expression on cardiomyocyte apoptosis in cardiac allograft rejection. The proposed experiments may provide new insights concerning the role of iNOS in pathobiology and potential therapy of cardiac allograft rejection and they may also be relevant to other cardiac diseases in which iNOS is expressed such as myocardial infarction and dilated cardiomyopathy.

描述（改编自申请人的摘要）： 在这项更新申请中提出的研究是调查以下因素的作用： 一氧化氮合酶（iNOS）的诱导型亚型在生物化学和 心脏移植排斥反应的病理生物学核心假设是 测试的是，在浸润心肌的巨噬细胞中由iNOS产生的NO 并在心肌细胞中增强心肌炎症， 导致心肌细胞死亡。我们已经证明：1）， 在内皮细胞中诱导iNOS mRNA、蛋白质和酶活性， 在排斥心脏同种异体移植物中浸润巨噬细胞和心肌细胞， 和2）iNOS诱导伴随心室功能受损， 心肌细胞坏死和凋亡引起的心肌细胞死亡。我们 现在提出研究坏死，凋亡， 心脏移植排斥反应中iNOS表达目标#1是调查， 使用培养的心肌细胞和大鼠和小鼠异位心脏 移植模型，假设激活聚腺苷5' - 二磷酸核糖合成酶（PARS）的一氧化氮有助于坏死 心肌细胞在体外和心脏移植排斥反应期间。目标#2 研究心肌炎症、坏死和 心脏移植排斥反应中的细胞凋亡得到改善， 不能表达iNOS的同种异体移植物供体和受体（iNOS-ko小鼠）。 目的#3是研究心肌细胞凋亡的假设， 由NO触发的可被半选择性iNOS抑制剂抑制， 用Bcl-2转染，并通过施用半胱天冬酶抑制剂。目标#4 探讨iNOS和考克斯-2在调节前列腺素 心脏移植排斥反应期间血栓素的合成， CD 154-CD 40相互作用对心肌细胞iNOS和考克斯-2表达的影响 考克斯-2表达对心肌细胞凋亡的影响 同种异体移植排斥反应。拟议的实验可能会提供新的见解 关于iNOS在心脏病的病理生物学和潜在治疗中的作用， 同种异体移植排斥反应，它们也可能与其他心脏疾病有关， iNOS在心肌梗死和扩张性心肌梗死中表达， 心肌病

项目成果

Increased immunoreactive endothelin-1 in human transplant coronary artery disease.

人类移植冠状动脉疾病中免疫反应性内皮素-1 增加。

• DOI: 10.1161/01.cir.94.9.2096
• 发表时间: 1996
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Ravalli,S;Szabolcs,M;Albala,A;Michler,RE;Cannon,PJ
• 通讯作者: Cannon,PJ

L-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice.

L-精氨酸可预防 LDL 受体敲除小鼠中的黄瘤发展并抑制动脉粥样硬化。

• DOI: 10.1161/01.cir.95.2.430
• 发表时间: 1997
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Aji,W;Ravalli,S;Szabolcs,M;Jiang,XC;Sciacca,RR;Michler,RE;Cannon,PJ
• 通讯作者: Cannon,PJ

Effects of inhibition of poly(adenosine diphosphate-ribose) synthase on acute cardiac allograft rejection.

聚（腺苷二磷酸核糖）合酶的抑制对急性心脏同种异体移植排斥的影响。

• DOI: 10.1097/01.tp.0000131662.01491.2e
• 发表时间: 2004
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Liu,Yulin;Son,NiHuiping;Szabolcs,MatthiasJ;Ma,Ninsheng;Sciacca,RobertR;Albala,Arline;Edwards,Niloo;Cannon,PaulJ
• 通讯作者: Cannon,PaulJ

Apoptosis of cardiac myocytes during cardiac allograft rejection. Relation to induction of nitric oxide synthase.

心脏同种异体移植排斥过程中心肌细胞的凋亡。

• DOI: 10.1161/01.cir.94.7.1665
• 发表时间: 1996
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Szabolcs,M;Michler,RE;Yang,X;Aji,W;Roy,D;Athan,E;Sciacca,RR;Minanov,OP;Cannon,PJ
• 通讯作者: Cannon,PJ

Apoptosis and increased expression of inducible nitric oxide synthase in human allograft rejection.

人同种异体移植排斥中诱导型一氧化氮合酶的凋亡和表达增加。

• DOI: 10.1097/00007890-199803270-00007
• 发表时间: 1998
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Szabolcs,MJ;Ravalli,S;Minanov,O;Sciacca,RR;Michler,RE;Cannon,PJ
• 通讯作者: Cannon,PJ