Intracellular Renin Inhibits Mitochondrial Permeability Transition Pore via Activated Mitochondrial Extracellular Signal-Regulated Kinase (ERK) 1/2 during Ischemia in Diabetic Hearts

Although beneficial effects of non-secreting intracellular renin (ns-renin) against ischemia have been reported, the precise mechanism remains unclear. In this study, we investigated the roles of ns-renin and mitochondrial extracellular signal-related kinase (ERK) 1/2 on mitochondrial permeability transition pore (mPTP) opening during ischemia in diabetes mellitus (DM) hearts. When isolated hearts from Wistar rats (non-DM hearts) and Goto-Kakizaki rats (DM hearts) were subjected to ischemia for 70 min by left anterior descending coronary artery ligation, DM hearts exhibited higher left ventricular (LV) developed pressure and lower LV end-diastolic pressure than non-DM hearts, suggesting ischemic resistance. In addition, DM hearts showed increased intracellular renin (int-renin, including secreting and non-secreting renin) in the ischemic area, and a direct renin inhibitor (DRI; aliskiren) attenuated ischemic resistance in DM hearts. ERK1/2 was significantly phosphorylated after ischemia in both whole cell and mitochondrial fractions in DM hearts. In isolated mitochondria from DM hearts, rat recombinant renin (r-renin) significantly phosphorylated mitochondrial ERK1/2, and hyperpolarized mitochondrial membrane potential (ΔΨm) in a U0126 (an inhibitor of mitogen-activated protein kinases/ERK kinases)-sensitive manner. R-renin also attenuated atractyloside (Atr, an mPTP opener)-induced ΔΨm depolarization and Atr-induced mitochondrial swelling in an U0126-sensitive manner in isolated mitochondria from DM hearts. Furthermore, U0126 attenuated ischemic resistance in DM hearts, whereas it did not alter the hemodynamics in non-DM hearts. Our results suggest that the increased int-renin during ischemia may inhibit mPTP opening through activation of mitochondrial ERK1/2, which may be involved in ischemic resistance in DM hearts

Recurrent Coronary Thrombus in a Patient with Chronic Immune Thrombocytopenia with Treatment Using Eltrombopag

Background. Eltrombopag, a nonpeptide thrombopoietin receptor agonist (TPO-RA), has been reported to be an effective therapy for chronic immune thrombocytopenia (ITP). However, a higher incidence of arterial and venous thromboembolic events was reported after using eltrombopag. Case Presentation. A 67-year-old man, treated with eltrombopag due to chronic ITP, was admitted due to acute coronary syndrome (ACS). Although coronary angiography revealed no occlusion, cardiac magnetic resonance imaging suggested a myocardial infarction in the territory of the left circumflex coronary artery. Three months after the ACS event, the obtuse marginal branches exhibited significant stenosis; hence, a percutaneous coronary intervention (PCI) was performed to implant a zotarolimus-eluting stent under the treatment of a dual antiplatelet therapy. However, stent thrombosis occurred 3 hours after PCI and required three other PCIs during the eltrombopag treatment. Conclusion. We present a case of an ITP patient, who experienced repeated coronary and stent thrombosis during the treatment with eltrombopag. We propose that the risk of ACS and consequent coronary stent thrombosis should be considered before the introduction of eltrombopag