Ischaemic post‐conditioning in rats: Responder and non‐responder differ in transcriptome of mitochondrial proteins

Ischaemic post‐conditioning (IPoC) is a clinical applicable procedure to reduce reperfusion injury. Non‐responsiveness to IPoC possibly caused by co‐morbidities limits its clinical attractiveness. We analysed differences in the expression of mitochondrial proteins between IPoC responder (IPoC‐R) and non‐responder (IPoC‐NR). Eighty rats were randomly grouped to sham, ischaemia/reperfusion (I/R), IPoC or ischaemic pre‐conditioning (IPC, as positive cardioprotective intervention) in vivo. Infarct sizes were quantified by plasma troponin I levels 60 minutes after reperfusion. After 7 days, rats were sacrificed and left ventricular tissue was taken for post hoc analysis. The transcriptome was analysed by qRT‐PCR and small RNA sequencing. Key findings were verified by immunoblots. I/R increased plasma troponin I levels compared to Sham. IPC reduced troponin I compared to I/R, whereas IPoC produced either excellent protection (IPoC‐R) or no protection (IPoC‐NR). Twenty‐one miRs were up‐regulated by I/R and modified by IPoC. qRT‐PCR analysis revealed that IPoC‐R differed from other groups by reduced expression of arginase‐2 and bax, whereas the mitochondrial uncoupling protein (UCP)‐2 was induced in IPC and IPoC‐R. IPoC‐R and IPoC‐NR synergistically increased the expression of non‐mitochondrial proteins like VEGF and SERCA2a independent of the infarct size. Cardiac function was more closely linked to differences in mitochondrial proteins than on regulation of calcium‐handling proteins. In conclusion, healthy rats could not always be protected by IPoC. IPoC‐NR displayed an incomplete responsiveness which is reflected by different changes in the mitochondrial transcriptome compared to IPoC‐R. This study underlines the importance of mitochondrial proteins for successful long‐term outcome.