Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis
Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis
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DOI：
10.1172/jci119736
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发表时间：
1997-10-15
影响因子：
15.9
通讯作者：
Pham, SM
中科院分区：
文献类型：
--
作者：
Shears, LL;Kawaharada, N;Pham, SM
在心脏移植中，慢性排斥表现为闭塞性血管病变。这种疾病的机制尚不清楚。本研究的目的是探讨一氧化氮（NO）在同种异体移植动脉硬化的发展中可能发挥的作用。来自 ACI 供体和 Wistar Furth 受体的大鼠同种异体移植物被用于移植，这些移植物在主要和次要组织相容性抗原上都具有很大的遗传差异。与同种移植物相比，28 天收集的同种异体移植物被发现诱导型一氧化氮合酶 (iNOS) mRNA 和蛋白质以及内膜厚度显着增加。用 iNOS 抑制剂抑制 NO 的产生使内膜增厚增加 57.2%，表明 NO 抑制同种异体移植动脉硬化的发展。接下来，我们评估了环孢素 (CsA) 对 iNOS 表达和同种异体移植动脉硬化的影响。 CsA (10 mg/kg/d) 抑制球囊诱导的主动脉损伤中 iNOS 的表达。同样，CsA 抑制同种异体主动脉移植物中 iNOS 的表达，使内膜增厚增加 65%。最后，我们研究了腺病毒介导的 iNOS 基因转移对同种异体移植物动脉硬化的影响。使用腺病毒载体进行 iNOS 转导，在未治疗的受体和接受 CsA 治疗的受体中完全抑制了同种异体移植物动脉硬化的发展。这些结果表明，早期免疫介导的 iNOS 表达上调部分保护同种异体主动脉移植物免于同种异体移植物动脉硬化的发展，并且 iNOS 基因转移策略可能有助于预防这种无法治疗的疾病过程的发展。
In cardiac transplantation, chronic rejection takes the form of an occlusive vasculopathy. The mechanism underlying this disorder remains unclear. The purpose of this study was to investigate the role nitric oxide (NO) may play in the development of allograft arteriosclerosis. Rat aortic allografts from ACI donors to Wistar Furth recipients with a strong genetic disparity in both major and minor histocompatibility antigens were used for transplantation. Allografts collected at 28 d were found to have significant increases in both inducible NO synthase (iNOS) mRNA and protein as well as in intimal thickness when compared with isografts. Inhibiting NO production with an iNOS inhibitor increased the intimal thickening by 57.2%, indicating that NO suppresses the development of allograft arteriosclerosis. Next, we evaluated the effect of cyclosporine (CsA) on iNOS expression and allograft arteriosclerosis. CsA (10 mg/kg/d) suppressed the expression of iNOS in response to balloon-induced aortic injury. Similarly, CsA inhibited iNOS expression in the aortic allografts, associated with a 65% increase in intimal thickening, Finally, we investigated the effect of adenoviral-mediated iNOS gene transfer on allograft arteriosclerosis. Transduction with iNOS using an adenoviral vector suppressed completely the development of allograft arteriosclerosis in both untreated recipients and recipients treated with CsA. These results suggest that the early immune-mediated upregulation in iNOS expression partially protects aortic allografts from the development of allograft arteriosclerosis, and that iNOS gene transfer strategies may prove useful in preventing the development of this otherwise untreatable disease process.