Role of HIF-1α in Cold Ischemia Injury of Rat Donor Heart Via the miR-21/PDCD4 Pathway

Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that plays a major role under hypoxia conditions. Cold storage during heart transplantation causes the donor heart long-term hypoxia. There is some evidence indicating a conceivable HIF-1α/microRNA-21 (miR-21)/phosphatase and tensin homolog (PTEN)/programmed cell death 4 (PDCD4) pathway. We assessed the hypothesis that HIF-1α has a positive effect during donor heart cold storage by making the miR-21 upregulate to reduce the expression of PDCD4.

We established the rat heart cold storage model and stratified it into 6-hour groups from 0 to 24 hours. Western blot and quantitative reverse transcription polymerase chain reaction were performed to detect the expression of HIF-1α, miR-21, PDCD4, and PTEN.

After cold storage the expression of HIF-1α increased from 0 to 6 hours and then gradually decreased, but the expression level was relatively higher compared with the control group. The miR-21 was upregulated from 0 to 12 hours then downregulated. The messenger RNA expression of PDCD4 was upregulated gradually, but the protein expression was significantly downregulated at 12th hour then continued to upregulate. Interestingly, the expression level of miR-21 was highest in the 12th hour, which indicated miR-21 could inhibit the PDCD4. We subsequently detected the messenger RNA of PTEN, which can inhibit HIF-1α and be inhibited by miR-21. The expression of PTEN was also significantly downregulated at the 12th hour.

In conclusion, there is possible interaction between HIF-1α and miR-21, and the conceivable HIF-1α/miR-21/PTEN/PDCD4 pathway plays a protective role in cold storage of the heart.