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

Terumori Satoh,Hideki Katoh,Prottoy Hasan,Yuichiro Maekawa,Masao Saotome,Daishi Nonaka,Hideharu Hayashi

doi:10.3390/ijms19010055

Terumori Satoh, Hideki Katoh + Show 5 more

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https://doi.org/10.3390/ijms19010055

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Abstract

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.

Highlights

It is widely accepted that the Renin-Angiotensin System (RAS) plays a central role in the pathogenesis of heart diseases, such as hypertension, cardiac hypertrophy, and heart failure [1]
When isolated hearts from diabetes mellitus (DM) rats were subjected to regional ischemia by left anterior descending (LAD) coronary artery ligation (Figure 1a), left ventricular (LV) developed pressure (LVDP) was higher (113 ± 3 mmHg, p < 0.05 vs. 90 ± 7 mmHg of non-DM hearts, Figure 1b), and LV end-diastolic pressure (LVEDP) was lower than those of non-DM hearts (10.3 ± 0.7 mmHg, p < 0.05 vs. 15.9 ± 0.8 mmHg of non-DM hearts, Figure 1c)
We evaluated the contribution of mitochondrial ERK1/2 to ischemic resistance in DM hearts using U0126

Summary

Introduction

It is widely accepted that the Renin-Angiotensin System (RAS) plays a central role in the pathogenesis of heart diseases, such as hypertension, cardiac hypertrophy, and heart failure [1]. Intensive recent investigations revealed that local RAS plays a significant pathophysiological role in heart disease. In the heart, emerging evidence has revealed that renin transcript codes for exon (1A-9) renin (non-secreting intracellular renin; ns-renin), which is derived from alternative renin transcript, is increased by myocardial infarction [2]. We and others reported that ns-renin increases in the myocardium after myocardial ischemia [2,3,4] and is involved in cardiac protection during ischemia [4,5,6]. The precise mechanism by which increased ns-renin protects the heart from ischemia remains unclear

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