Remote Ischemic Conditioning Improves Post-Ischemic Cardiac Function: The Role of Neuregulin-1

Background: There is substantial evidence that remote ischemic conditioning (RIC) induced by repeated episodes of transient limb ischemia is a clinically applicable method for protecting the heart against acute ischemia and reperfusion (IR) injury as well as it improves post-ischemic cardiac function. Neuregulin-1 (NRG-1)/ErbB2 and ErbB4 signaling pathway is critical for cardiac development and repair with therapeutic potential for reverse left ventricle remodelling and heart failure. The present study aimed to investigate the effect of remote conditioning on post-ischemic cardiac function in association with the plasma levels of NRG-1.

Methods: Adult male anaesthetized OFA-1 rats were subjected to 30 minute left coronary artery occlusion followed by 21 days reperfusion and allocated to (1) sham operated (without occlusion; n = 4); (2) IR (n = 6) and (3) IR+RIC (3 cycles of 5 minutes of hind limb ischemia, 5 minutes of reperfusion, started at 5^th min of index ischemia; n = 7). Functional parameters on the heart such as cardiac output (CO) and external heart work (EHW) were evaluated on an isolated erythrocyte-perfused working heart model. Plasma level of NRG-1 was measured by ELISA.

Results: Myocardial infarction resulted in significant increase of left ventricle/body weight ratio compared with sham operated group (p < 0.05). This was in line with the reduction in CO (29.6 ± 1.6 mL/min/g heart vs. 43.7 ± 1 mL/min/g heart, p < 0.01) and EHW (12.8 ± 0.3 mL*mm Hg/g heart vs. 21.1 ± 0.7 mL*mm Hg/g heart). Plasma concentration of NRG-1 was significantly dropped following IR (2.1 ± 0.5 vs. 6.1 ± 0.6 ng/µL, p < 0.05). RIC markedly improved post-infarcted cardiac function compared with IR group (CO: 39.5 ± 1.6 mL/min/g heart and EHW: 17.8 ± 0.9 mL*mm Hg/g heart, p < 0.05, respectively) in association with the increase of plasma NRG-1 concentration (4.3 ± 0.5 ng/µL).

Conclusion: Our data demonstrated for the first time that improvement of cardiac function following ischemia and 21 days reperfusion by RIC is strongly associated with plasma concentration of NRG-1. This findings might represent a novel cardioprotective effect of RIC mediated via up-regulation of NRG-1.