Remote Ischemic Preconditioning Contributes to the Expression of Long Non-Coding RNA H19 and Hypoxia-Inducible Factor-1α during Isolated Coronary Artery Bypass Graft Surgery in Patients with Ischemic Heart Disease
Abstract
The aim. The aim of our study was to establish the expression levels of long non-coding RNA H19 and hypoxiainducible factor-1α (HIF-1α) in the myocardium and leukocyte fraction as a possible mechanism of adaptation to remote ischemic preconditioning (RIPC) in patients with ischemic heart disease during off-pump isolated coronary artery bypass grafting.
Methods. To assess hemodynamic parameters, data from 31 patients (14 in the RIPC group, 17 in control group) were analyzed. The RIPC procedure was performed in patients before surgery by applying a blood pressure cuff to the right forearm. The cuff was inflated to a pressure of 200 mmHg and left for 5 minutes. This was followed by a reperfusion step which lasted 5 minutes. Periods of ischemia and reperfusion lasting 5 minutes were repeated three times. The expression level of long non-coding RNA H19 and HIF-1α was determined in the myocardium and leukocyte fraction by real-time polymerase chain reaction.
Results. At the stage of formation of distal anastomoses in patients with RIPC cardiac index (CI) was 24% higher, and stroke volume index (SVI) was 18% higher. Systemic vascular resistance index (SVRI) was significantly lower in patients of the RIPC group (p <0.05). At the end of the operation the CI and SVI levels were significantly higher in the RIPC group, and the rate of SVRI in the RIPC group was significantly lower. In patients with RIPC the expression of H19 in the leukocyte fraction increased by a factor of 3 and in myocardial tissues the level of H19 expression decreased by a factor of 6.7 (p <0.05). The expression of HIF-1α in the myocardium after ischemic preconditioning significantly decreased by a factor of 7.5 (p <0.05), but in the leukocyte fraction there was an insignificant decrease in HIF-1α expression by 20% (p > 0.05).
Conclusions. Based on hemodynamic parameters, it can be concluded that patients with RIPC were more hemodynamically stable. Significant changes in the expression of long non-coding RNA H19 and hypoxia-inducible factor-1α demonstrate the importance of these molecules in adaptation to ischemic preconditioning. However, the mechanisms of RIPC involving H19 and HIF-1α need further study.
References
- Ong SG, Hausenloy DJ. Hypoxia-inducible factor as a therapeutic target for cardioprotection. Pharmacol Ther. 2012;136(1):69-81. https://doi.org/10.1016/j.phar-mthera.2012.07.005
- Cai Z, Manalo DJ, Wei G, Rodriguez ER, Fox-Talbot K, Lu H, et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation. 2003;108(1):79-85. https://doi.org/10.1161/01.CIR.0000078635.89229.8A
- Wu W, Hu Q, Nie E, Yu T, Wu Y, Zhi T, et al. Hypoxia induces H19 expression through direct and indirect Hif-1α activity, promoting oncogenic effects in glioblastoma. Sci Rep. 2017;7:45029. https://doi.org/10.1038/srep45029.
- Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, et al. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res. 1993;72(6):1293-9. https://doi.org/10.1161/01.res.72.6.1293
- Prabhakar NR, Semenza GL. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev. 2012;92(3):967-1003. https://doi.org/10.1152/physrev.00030.2011
- Heusch G. HIF-1α and paradoxical phenomena in cardioprotection. Cardiovasc Res. 2012;96(2):214-5. https://doi.org/10.1093/cvr/cvs145
- Loor G, Schumacker PT. Role of hypoxia-inducible factor in cell survival during myocardial ischemia-reperfusion. Cell Death Differ. 2008;15(4):686-90. https://doi.org/10.1038/cdd.2008.13
- Eckle T, Kohler D, Lehmann R, El Kasmi K, Eltzschig HK. Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning. Circulation. 2008;118(2):166-75. https://doi.org/10.1161/CIRCULATIONAHA.107.758516
- Sarkar K, Cai Z, Gupta R, Parajuli N, Fox-Talbot K, Darshan MS, et al. Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning. Proc Natl Acad Sci USA. 2012;109(26):10504-9. https://doi.org/10.1073/pnas.1208314109