HIF-1alpha 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) 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.