Abstract 11993: Intracellular Renin Preserves Mitochondrial Function and Protects Cardiomyocytes From Ischemic Injury in Diabetic Heart
Purpose: Cardiac myocytes express intracellular renin, which is different from circulating renin, and this type of renin increased after myocardial infarction. However, the role of intracellular renin is unknown. We investigated the distribution and expression of intracellular renin after ischemia and the effects of intracellular renin on ischemic cell injury in diabetic heart.
Methods: In Goto-Kakizaki (DM) and Wistar (non-DM) rats, Langendorff-perfused heart was subjected to ischemia by coronary artery ligation for 90 min. Direct renin inhibitor, aliskiren (DRI; 1μM), and angiotensin II type 1 receptor antagonist, valsartan (ARB; 0.1μM), were perfused before ischemia. Infarct size (IS) and expression of RAS components (Western blot analysis (WB) and immunohistochemistry (IHC)) were examined. For the assessment of mitochondrial function, we measured expression of uncoupling protein-2 (UCP-2), NAD+/NADH ratio and ATP concentration. Mitochondrial membrane potential (ΔΨm) was measured in isolated mitochondria or myocytes.
Results: (1) In DM, reduction of left ventricular developed pressure (LVDP) and elevation of end diastolic pressure (EDP) during ischemia were prevented, and IS was significantly smaller than non-DM (41% vs 54%, p≤0.05). (2) DRI but not ARB deteriorated cardiac function (LVDP and EDP) and increased IS in DM. (3) WB and IHC showed that renin expression in the ischemic area was significantly increased in DM. Angiotensin II was slightly increased in DM. The expression of (pro)renin receptor was not different between two groups. Electron microscope analysis showed that renin was predominantly localized within mitochondria. (4) Ischemia-induced UCP-2 expression was reduced in DM compared to non-DM. (5) Exposure of renin to permeabilized myocytes or isolated mitochondria hyperpolarized ΔΨm, and accelerated NAD+/NADH ratio in mitochondria and increased ATP concentration in myocytes. The effect of renin on ΔΨm was inhibited by DRI but not by ARB.
Conclusions: During ischemia, expression of intracellular renin, which localizes within mitochondria, was induced in DM. Intracellular renin could afford protective effect against ischemic injury by preventing depolarization of ΔΨm and increasing ATP in diabetic heart.
- © 2013 by American Heart Association, Inc.