RISK and SAFE signaling pathway interactions in remote limb ischemic perconditioning in combination with local ischemic postconditioning

Abstract

Local ischemic postconditioning (IPost) and remote ischemic perconditioning (RIPer) are promising methods to decrease ischemia-reperfusion (I/R) injury. We tested whether the use of the two procedures in combination led to an improvement in cardioprotection through a higher activation of survival signaling pathways. Rats exposed to myocardial I/R were allocated to one of the following four groups: Control, no intervention at myocardial reperfusion; IPost, three cycles of 10-s coronary artery occlusion followed by 10-s reperfusion applied at the onset of myocardial reperfusion; RIPer, 10-min limb ischemia followed by 10-min reperfusion initiated 20 min after coronary artery occlusion; IPost+RIPer, IPost and RIPer in combination. Infarct size was significantly reduced in both IPost and RIPer (34.25 ± 3.36 and 24.69 ± 6.02%, respectively) groups compared to Control (54.93 ± 6.46%, both p < 0.05). IPost+RIPer (infarct size = 18.04 ± 4.86%) was significantly more cardioprotective than IPost alone (p < 0.05). RISK pathway (Akt, ERK1/2, and GSK-3β) activation was enhanced in IPost, RIPer, and IPost+RIPer groups compared to Control. IPost+RIPer did not enhance RISK pathway activation as compared to IPost alone, but instead increased phospho-STAT-3 levels, highlighting the crucial role of the SAFE pathway. In IPost+RIPer, a SAFE inhibitor (AG490) abolished cardioprotection and blocked both Akt and GSK-3β phosphorylations, whereas RISK inhibitors (wortmannin or U0126) abolished cardioprotection and blocked STAT-3 phosphorylation. In our experimental model, the combination of IPost and RIPer improved cardioprotection through the recruitment of the SAFE pathway. Our findings also indicate that cross talk exists between the RISK and SAFE pathways.

Mechanically Unloading the Left Ventricle Before Coronary Reperfusion Reduces Left Ventricular Wall Stress and Myocardial Infarct Size

“…Alternatively, the generation of repeated periods of myocardial ischemia and reperfusion with balloon angioplasty, known as ischemic conditioning, has also been shown to promote activity of the RISK pathway. [14][15][16] Although promising, critical barriers to these cardioprotective strategies include the multifactorial nature of reperfusion injury, thereby limiting the impact of a single-target pharmacological strategy; the potential for coronary vascular injury (dissection or perforation) with ischemic conditioning; and the mandate for rapid coronary reperfusion and thus insufficient time for a drug to penetrate into myocardial injury zones. A need exists for improved cardioprotective strategies that broadly affect the multiple levels of reperfusion injury without causing further myocardial damage.…”

Efeito protetor do per-condicionamento isquêmico remoto nas lesões da síndrome de isquemia e reperfusão renal em ratos

“…They appear to be linked to the activation of the RISK (reperfusion Injury Yamaki Yamaki Yamaki Yamaki Yamaki Protective effect of remote ischemic per-conditioning in the ischemia and reperfusion-induce renal injury in rats Salvage Kinase), through phosphatidylinositol 3-kinase (PI3K)-Akt and the mitogen-activated protein kinase p44/ p42, besides ERK 1/2 (Extracellular Signal-Regulated Kinase). It was also demonstrated the involvement of ATPdependent potassium channels, of adenosine and the SAFE(Survivor Activating Factor Enhancement) pathway 5,9,10,12 . Although these Remote ischemic conditioning techniques possess interweaving mechanisms, the rPreC has limited clinical applicability, since it is usually impossible to predict when an organ will suffer from an ischemic event.…”

Novel adjunctive treatments of myocardial infarction

“…They include the reperfusion-injury salvage kinase [24] and survivor activating factor enhancement [25,26] signaling pathways. Furthermore, RIC modifies systemic inflammatory response [27,28] , prevents endothelial dysfunction [29] and platelet activation [30] following ischemia-reperfusion injury.…”