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

Aims: To investigate whether hypoxia-inducible factor (HIF) 1 alpha 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-1 alpha Delta ODD-expressing adenovirus which can functionally and steadily express HIF-1 alpha during normoxia and transfected human cardiomyocytes (HCMs) to investigate whether HIF-1 alpha, as a single factor, can upregulate MICA/B expression. Alternatively, HCMs were treated with HIF-1 alpha 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-1 alpha overexpression in normoxia, and inhibited by HIF-1 alpha RNAi treatment during hypoxia-reoxygenation (H/R). NK cytotoxicity towards HCMs shows a positive correlation with HIF-1 alpha expression. Moreover, CsA can inhibit HIF-1 alpha and MICB expression but upregulates MICA expression during H/R. Significance: These findings suggest that proper control of HIF-1 alpha 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. (c) 2010 Elsevier Inc. All rights reserved.