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HIF-1alpha accumulation upregulates MICA and MICB expression on human cardiomyocytes and enhances NK cell cytotoxicity during hypoxia-reoxygenation.

机译:HIF-1alpha积累上调人心肌细胞上的MICA和MICB表达,并增强缺氧-复氧过程中NK细胞的细胞毒性。

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摘要

AIMS: To investigate whether hypoxia-inducible factor (HIF) 1alpha and cyclosporin A (CsA) can regulate MICA/B expression and affect NK cytotoxicity during ischemia/reperfusion (I/R) injury. MAIN METHODS: We generated an HIF-1alphaDeltaODD-expressing adenovirus which can functionally and steadily express HIF-1alpha during normoxia and transfected human cardiomyocytes (HCMs) to investigate whether HIF-1alpha, as a single factor, can upregulate MICA/B expression. Alternatively, HCMs were treated with HIF-1alpha RNAi or CsA, and then cultured under hypoxia/reoxygenation (H/R) condition to simulate I/R injury in vitro. Cells were collected at different time points and used for studies of gene expression and NK cytotoxicity. KEY FINDINGS: Expression of MICA/B in HCMs is upregulated through HIF-1alpha overexpression in normoxia, and inhibited by HIF-1alpha RNAi treatment during hypoxia-reoxygenation (H/R). NK cytotoxicity towards HCMs shows a positive correlation with HIF-1alpha expression. Moreover, CsA can inhibit HIF-1alpha and MICB expression but upregulates MICA expression during H/R. SIGNIFICANCE: These findings suggest that proper control of HIF-1alpha expression via CsA dose may be a potential therapeutic approach for avoiding MIC expression, and improving the function and long-term survival of heart allografts.
机译:目的:探讨缺氧诱导因子(HIF)1α和环孢菌素A(CsA)是否可以调节缺血/再灌注(I / R)损伤期间的MICA / B表达并影响NK细胞毒性。主要方法:我们产生了一种表达HIF-1alphaDeltaODD的腺病毒,该腺病毒可以在常氧期间正常且稳定地表达HIF-1alpha,并转染了人类心肌细胞(HCM),以研究HIF-1alpha作为单个因子是否可以上调MICA / B表达。或者,用HIF-1alpha RNAi或CsA处理HCM,然后在缺氧/复氧(H / R)条件下培养,以在体外模拟I / R损伤。在不同时间点收集细胞,用于研究基因表达和NK细胞毒性。主要发现:常氧中HICA-1B的过表达会上调HICAs中MICA / B的表达,而缺氧-复氧(H / R)期间HIF-1alpha RNAi会抑制MICA / B的表达。 NK对HCM的细胞毒性与HIF-1alpha表达呈正相关。此外,CsA可以抑制HIF-1alpha和MICB表达,但在H / R期间上调MICA表达。意义:这些发现表明,通过CsA剂量适当控制HIF-1alpha表达可能是避免MIC表达,改善心脏同种异体移植物功能和长期存活的潜在治疗方法。

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