Heme Oxygenase-1 and Preconditioning
Remote ischemic preconditioning (RIPC), applying intermittent ischemic stimulus at a remote organ (mostly limb) before myocardial ischemia, has been proven to effective in alleviating myocardial apoptosis, improving cardiac function recovery, decreasing the incidence of reperfusion arrhythmia, and reducing post-ischemic myocardial infarct size (IS) in various animal models. This cardioprotective potential has also been successfully translated into adult patients undergoing cardiovascular surgery. Previous animal, human volunteer, and human cardiac surgical studies have established that RIPC presents the protective effect in two different phases: early (<4 h) and delayed (24-72 h) phase. In early protection, activation of reperfusion injury salvage kinases pathway including phosphatidylinositol 3-kinase,kinase B/AKt and extracellular signal-regulated kinases 1 and 2, and/or Survivor Activating Factor enhancement pathway have been widely accepted as the contributing mechanisms.
Protective role of HO-1 in ischemia reperfusion (I/R) injury has been elucidated in myocardial ischemic preconditioning, hepatic ischemic preconditioning and RIPC, and also in cerebral pharmacologic post-conditioning.
In a previous study with Langendorff-perfused isolated rat hearts, it was found that HO-1 was involved in the cardioprotection induced by DRIPC; increasing in the number of preconditioning stimuli may obtain an enhanced cardioprotective effect accompanied by increased HO-1 level. Various strategies have been proposed to reduce I/R injury, including ischemic pre- and post-conditioning. Despite these two invasive methods have been recognized as the most powerful interventions, remote ischemic preconditioning has also been proven to have similar efficacy in protecting the myocardium from I/R injury in animal models. Further clinical trials have confirmed the efficacy of RIPC-mediated cardioprotection in patients undergoing cardiac surgery (adult and children) or percutaneous coronary intervention. The duration of protection conferred by RIPC in the delayed phase is 24-72 h before index myocardial ischemia. A time-dependent increase in HO-1 level was observed within 24 h (4, 8, and 24 h) after hepatic RIPC. In a recent study, remote preconditioning was applied once per day within 3 d and explored the potential additive effect by increasing the circles of stimuli. In the three different time interval preconditioning groups, an enhanced protection was observed, which was correlated with enhanced expression of HO-1, a molecule that has been shown to have cellular protection in diabetes, or in aging animal model. Cardioprotection by DRIPC may be preserved in diabetes or aging population that is associated with reduced myocardial HO-1. The transcriptional regulation of HO-1 is partly mediated by the nuclear factor erythroid 2-related factor 2/antioxidant response element signal pathway, which has been recognized as a contributing factor in delayed cardioprotection by H2S or hypoxic preconditioning. As the main components of reperfusion injury, salvage kinases pathway in RIPC-induced cardioprotection, phosphatidylinositol 3-kinaseeprotein kinase B/AKt, protein kinase C, and extracellular signal-regulated kinases 1 and 2 pathways are also involved in the upstream regulation of nuclear factor erythroid 2e related factor 2/antioxidant response element pathway. Additionally, in previous laboratory studies, the important role of nitric oxide synthase (NOS) in cardioprotection by delayed RIPC has been proven by using inducible nitric oxide synthase (iNOS) knockout technique, and NOS inhibitor (L-NAME). Several indications also came from animal or human study findings showing an increase in myocardial iNOS mRNA level in remote preconditioned hearts. In coxsackie virus B3-induced mouse model of chronic myocarditis, inhibition of NO/iNOS by LNAME could downregulate HO-1 protein level, indicating an NO/HO-1 pathway in cardioprotection. Using a Langendorff model, our study confirmed that HO-1 is a novel potential contributing mechanism in the cardioprotection by DRIPC.
Recently, the role of heme oxygenase 1 (HO-1) in delayed preconditioning has been indicated in RIPC-induced hepatic protection and H2S-induced cardioprotection, in addition, DRIPC was also found to increase HO-1 protein expression. It was addressed that the combination of DRIPC and Sevoflurane Postconditioning (SPoC) could offer a superior cardioprotective potential than SPoC or DRIPC alone via enhanced HO-1 level, partly through Nrf2 nuclear translocation. Both SPoC and DRIPC could offer protection from myocardial I/R injury. Moreover, we showed that DRIPC produced an additive effect to SPoC, as evidenced by significantly increased cardiac function recovery, reduced cTnI release, and in particular the limited IS. Enhancement of HO-1 expression, but not RISK pathway, in reperfused myocardium may play an important role, despite the controversy, RISK pathway (PKB/AKt and/ or ERK1/2) has been recognized as an important mechanism in the cardioprotective conditioning, including SPoC. It was found that DRIPC mediated cardioprotection through the expression of HO-1. Moreover, the HO-1 level was further increased by adding DRIPC to SPoC, indicating its contributing role in the enhanced cardioprotection, and although HO-1 level was not increased in the SPoC group a synergistic increase was shown in the DRIPC + SPoC group. DRIPC was shown to induce cardioprotection by promoting the translocation of Nrf2 into the nucleus. This process was supported by correlation analysis, revealing a positive relationship between Nrf2 translocation and HO-1 protein expression, and such involvement of Nrf2 in cardioprotective effect was further suggested by the similar trend between the protein expression level and mRNA level of HO-1.