学位論文 Intracellular renin protects cardiomyocytes from ischemic injury in diabetic heart

Nonaka, Daishi

内容記述
Background: Local Renin-Angiotensin-Aldosterone system (RAS) is important in cardiac pathophysiology. We investigated the expression and distribution of intracellular renin after ischemia, and the effects of renin on mitochondrial function in diabetic heart. Methods: In Goto-Kakizaki (DM) and Wistar (non-DM) rats, Langendorff-perfused hearts were subjected to ischemia by coronary artery ligation for 90 min. Infarct Size (IS) and expression of RAS components were examined. Mitochondrial membrane potential (ΔΨm), uncoupling protein-2 (UCP2), NAD/NADH ratio, and ATP were measured in renin-treated myocytes or isolated mitochondria. Results: After ischemia, LV function (LVDP; 76 ± 4 vs. 52 ± 4 mmHg, LVEDP; 18 ± 2 vs. 29 ± 4 mmHg, p<0.05, DM; n=9, non-DM; n=9, respectively) was prevented and IS (44.2 ± 2.1 vs. 53.7 ± 2.9 %, p<0.05) was significantly small in DM hearts. These cardioprotective effects were abolished when DM hearts were treated with direct renin inhibitor (LVDP; 77 ± 3 vs. 55 ± 4 mmHg, LVEDP; 16 ± 1 vs. 27 ± 3 mmHg, IS; 40.8 ± 2.9 vs. 52.1 ± 3.4 %, p<0.05, DM; n=5, DM plus DRI; n=5, respectively). Renin expression in the ischemic area was increased in DM hearts. Electron microscopy showed predominant renin localization within mitochondria. In permeabilized myocytes or isolated mitochondria, renin hyperpolarized ΔΨm, increased NAD/NADH ratio and preserved ATP content. Ischemiainduced UCP2 expression was reduced in DM. Conclusions: Intracellular renin, which mainly localizes within mitochondria, increased during ischemia and protected cardiomyocytes in diabetic hearts. This protective effect of renin is at least partially because of the reduction of UCP2 and the acceleration of electron transport chain, which resulted in the prevention of mitochondrial depolarization and ATP production.
doctoral
医学系研究科
甲第716号
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