Mitochondrial ATP-sensitive K+channels play a role in cardioprotection by Na+-H+exchange inhibition against ischemia/reperfusion injury

AbstractOBJECTIVESThe possible role of the ATP-sensitive potassium (KATP) channel in cardioprotection by Na+-H+exchange (NHE) inhibition was examined.BACKGROUNDThe KATPchannel is suggested to be involved not only in ischemic preconditioning but also in some pharmacological cardioprotection.METHODSInfarction was induced by 30-min coronary occlusion in rabbit hearts in situ or by 30-min global ischemia in isolated hearts. Myocardial stunning was induced by five episodes of 5-min ischemia/5-min reperfusion in situ. In these models, the effects of NHE inhibitors (cariporide and ethylisopropyl-amiloride [EIPA]) and the changes caused by KATPchannel blockers were assessed. In another series of experiments, the effects of EIPA on mitochondrial KATP(mito-KATP) and sarcolemmal KATP(sarc-KATP) channels were examined in isolated cardiomyocytes.RESULTSCariporide (0.6 mg/kg) reduced infarct size in situ by 40%, and this effect was abolished by glibenclamide (0.3 mg/kg), a nonselective KATPchannel blocker. In vitro, 1 μM cariporide limited infarct size by 90%, and this effect was blocked by 5-hydroxydecanoate (5-HD), a mito-KATPchannel blocker but not by HMR1098, a sarc-KATPchannel blocker. Infarct size limitation by 1 μM EIPA was also prevented by 5-HD. Cariporide attenuated regional contractile dysfunction by stunning, and this protection was abolished by glibenclamide and 5-HD. Ethylisopropyl amiloride neither activated the mito-KATPchannel nor enhanced activation of this channel by diazoxide, a KATPchannel opener.CONCLUSIONSOpening of the mito-KATPchannel contributes to cardioprotection by NHE inhibition, though the interaction between NHE and this KATPchannel remains unclear

虚血プレコンディショニングの心筋細胞保護機構とその臨床応用

To develop novel strategies for protection of cardiomyocytes from ischemia/reperfusion injury, we have analyzed cytoprotective mechanisms of ischemic preconditioning (PC). PC, a form of adaptation, refers to enhancement of myocardial tolerance against ischemia/reperfusion-induced necrosis by exposing the myocardium to a brief episode of non-lethal ischemia. PC induces the generation of agonists of Gi/Gq protein-coupled receptors and release of TNF-α and HB-EGF. Stimulation of receptors of these agonists provokes activation of multiple signal pathways, including PKC-ε and PI3K/Akt pathways, which ultimately reach to the “end-effector” of cardiomyocyte protection. There are three possible effectors in PC, mitochondrial ATP-sensitive K+ channel (mKATP channel), glycogen synthase kinase-3β (GSK-3β) and connexin-43 (Cx43). Activation of the mKATP channel attenuates mitochondrial dysfunction presumably by suppressing mitochondrial Ca2+ overload during ischemia/reperfusion. The level of phospho-(Ser9)-GSK-3β, a suppressor of mitochondrial permeability transition upon reperfusion, was found to be a determinant of infarct size in vivo. Accelerated closure of the gap junction after the onset of ischemia by PKC- and ERK-mediated Cx43 phosphorylation is suggested to be an adjunctive mechanism of protection, which suppresses propagation of myocyte injury within the area at risk. However, the cytoprotective signaling of PC can be impaired by concurrent diseases such as postinfarct ventricular remodeling. An opener of the mKATP channel is currently being used for myocardial protection, and selective GSK-3β inhibitors are candidates for novel therapy. Further characterization of cytoprotective signaling and effector molecules and elucidation of their modifications by co-morbidity are necessary for the development of clinically applicable agents

Retrospective Efficacy Analysis of Immune Checkpoint Inhibitor Rechallenge in Patients with Non-Small Cell Lung Cancer

Little is known regarding the effectiveness and tolerability of immune checkpoint inhibitor (ICI) rechallenge after disease progression following initial ICI treatments. To identify eligible patients for ICI rechallenge, we retrospectively analyzed the relationship between clinical profiles and the effect of ICI rechallenge in patients with non-small cell lung cancer (NSCLC). We enrolled 35 NSCLC patients at six different institutions who were retreated with ICIs after discontinued initial ICI treatments due to disease progression. Cox proportional hazards models were used to assess the impact of clinical profiles on overall survival (OS) and progression-free survival (PFS). Median PFS and OS were 81 d (95% confidence interval, CI, 41–112 d) and 225 d (95% CI 106–361 d), respectively. The objective response rate was 2.9%, and the disease control rate was 42.9%. Multivariate analysis demonstrated that Eastern Cooperative Oncology Group Performance Score (ECOG-PS) ≥ 2 (hazard ratio, HR, 2.38; 95% CI 1.03–5.52; p = 0.043) and body mass index (BMI) > 20 (HR 0.43, 95% CI 0.19–0.95, p = 0.036) were significantly associated with PFS of ICI rechallenge. Our observations suggest that poor ECOG-PS and low BMI at intervention with ICI rechallenge may be negative predictors for ICI rechallenge treatment in patients with NSCLC