Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts

Masashi Mizuno, Atsushi Kuno, Toshiyuki Yano, Takayuki Miki, Hiroto Oshima, Tatsuya Sato, Kei Nakata, Yukishige Kimura, Masaya Tanno, Tetsuji Miura, Masashi Mizuno, Atsushi Kuno, Toshiyuki Yano, Takayuki Miki, Hiroto Oshima, Tatsuya Sato, Kei Nakata, Yukishige Kimura, Masaya Tanno, Tetsuji Miura

Abstract

To explore mechanisms by which SGLT2 inhibitors protect diabetic hearts from heart failure, we examined the effect of empagliflozin (Empa) on the ultrastructure of cardiomyocytes in the noninfarcted region of the diabetic heart after myocardial infarction (MI). OLETF, a rat model of type 2 diabetes, and its nondiabetic control, LETO, received a sham operation or left coronary artery ligation 12 h before tissue sampling. Tissues were sampled from the posterior ventricle (i.e., the remote noninfarcted region in rats with MI). The number of mitochondria was larger and small mitochondria were more prevalent in OLETF than in LETO. Fis1 expression level was higher in OLETF than in LETO, while phospho-Ser637-Drp1, total Drp1, Mfn1/2, and OPA1 levels were comparable. MI further reduced the size of mitochondria with increased Drp1-Ser616 phosphorylation in OLETF. The number of autophagic vacuoles was unchanged after MI in LETO but was decreased in OLETF. Lipid droplets in cardiomyocytes and tissue triglycerides were increased in OLETF. Empa administration (10 mg/kg per day) reduced blood glucose and triglycerides and paradoxically increased lipid droplets in cardiomyocytes in OLETF. Empa suppressed Fis1 upregulation, increased Bnip3 expression, and prevented reduction in both mitochondrial size and autophagic vacuole number after MI in OLETF. Together with the results of our parallel study showing upregulation of SOD2 and catalase by Empa, the results indicate that Empa normalizes the size and number of mitochondria in diabetic hearts and that diabetes-induced excessive reduction in mitochondrial size after MI was prevented by Empa via suppression of ROS and restoration of autophagy.

Keywords: Acute myocardial infarction; SGLT2 inhibitor; diabetes mellitus; empagliflozin; mitochondria.

© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Figures

Figure 1
Figure 1
Effects of myocardial infarction and empagliflozin on mitochondrial number and size in the noninfarcted region of LETO and OLETF. (A) Representative electron micrographs from the noninfarcted myocardium of LETO, OLETF treated with a vehicle, and OLETF treated with empagliflozin (Empa) that were subjected to a sham operation or coronary artery ligation (MI). Scale bar = 2 μm. Summary data of the percentage of total mitochondrial area (B), mitochondrial number per area (C), and the area of individual mitochondria (D) in 6 groups are shown. Ten images were taken from each heart, and data for 5–6 rats in each group were analyzed. *P < 0.05.
Figure 2
Figure 2
Frequency distribution analysis of individual mitochondrial areas: LETO versus OLETF. (A) Frequency distributions of areas of individual mitochondria in rats subjected to a sham operation. Pie charts show the proportion of mitochondria less than 0.20 μm2 in each group. *P < 0.05 by the z‐test. (B) Frequency distributions of areas of individual mitochondria in rats subjected to coronary artery ligation (MI). Pie charts show proportion of mitochondria less than 0.54 μm2 in each group. In each group, 2364 (LETO Sham), 2505 (OLETF Sham), 2466 (OLETF‐Empa‐Sham), 2546 (LETO‐MI), 2269 (OLETF‐MI), and 2201 (OLETF‐Empa‐MI) mitochondria from 50 to 60 images were analyzed. *P < 0.05 by the z‐test. NS = not significant.
Figure 3
Figure 3
Frequency distribution analysis of impacts of myocardial infarction on mitochondrial size in the noninfarcted myocardium in LETO and OLETF. Comparisons of frequency distribution of individual mitochondrial area between the sham and myocardial infarction (MI) groups in LETO (A), OLETF treated with a vehicle (B), and empagliflozin (Empa)‐treated OLETF (C). Vertical dashed lines indicate a median value (0.54 μm2) of mitochondrial size in the LETO sham group, and pie charts show the proportion of mitochondria less than 0.54 μm2 in each group. As in Figure 2, 2364 (LETO Sham), 2505 (OLETF Sham), 2466 (OLETF‐Empa‐Sham), 2.546 (LETO‐MI), 2269 (OLETF‐MI), and 2201 (OLETF‐Empa‐MI) mitochondria from 50 to 60 images were analyzed in each group. *P < 0.05 by the z‐test. NS, not significant.
Figure 4
Figure 4
Effect of empagliflozin on autophagic vacuoles in noninfarcted myocardium. (A and B) Representative electron micrographs of autophagic vacuoles in the myocardium observed in LETO after the sham operation (A) and OLETF treated with a vehicle after the sham operation (B). Arrows indicate autophagic vacuoles. N = nucleus. (C) Average of the number of autophagic vacuoles per area in the myocardium from six groups of rats. Five images were taken from each heart, and data for five or six rats in each group were analyzed. *P < 0.05.
Figure 5
Figure 5
Effects of myocardial infarction on regulatory factors of mitochondrial fission. (A) Representative immunoblots for Fis1 in the noninfarct remote myocardium from LETO, OLETF treated with a vehicle, and OLETF treated with empagliflozin (Empa) that were subjected to a sham operation or coronary artery ligation (MI). (B) Summary data of Fis1 protein level normalized to vinculin. (C) Representative immunoblots for phospho‐Ser616‐Drp1 and total Drp1 in the noninfarcted myocardium from rats of six groups. (D) Summary data of levels of phospho‐Ser616‐Drp1 and total Drp1. (E) Representative immunoblots for phospho‐Ser637‐Drp1 and total Drp1. (F) Summary data of phospho‐Ser637‐Drp1 and total Drp1 normalized to vinculin level. N = 8 in each group. *P < 0.05. a.u., arbitrary unit.
Figure 6
Figure 6
Effects of myocardial infarction on regulatory factors of mitochondrial fusion. (A) Representative immunoblots for mitofusin 1 (Mfn1) in the noninfarcted myocardium in LETO and in OLETF treated with either a vehicle or empagliflozin (Empa) that were subjected to a sham operation or coronary ligation (MI). (B) Summary data of Mfn1 protein levels normalized to vinculin. (C) Representative immunoblots for Mfn2. (D) Summary data of Mfn2 protein levels. (E) Representative immunoblot for OPA1. L‐OPA1: longer form of OPA1. S‐OPA1: shorter and soluble form of OPA1. The blot of vinculin is identical to that in (C) because blots of both Mfn2 and OPA1 were from the same membrane. (F) Summary data for quantification of L‐OPA1 and S‐OPA1 normalized to vinculin. N = 8 in each group.
Figure 7
Figure 7
Alterations in Bnip3 and Parkin after myocardial infarction. (A) Representative immunoblots for Bnip3 in the noninfarcted myocardium in LETO and in OLETF treated with either a vehicle or empagliflozin (Empa) that were subjected to a sham operation or coronary ligation (MI). (B) Summary data of Bnip3 protein levels normalized to vinculin. N = 8 in each group. (C) Quantification of mRNA levels of Bnip3 in the myocardium. N = 8 in each group. (D) Parkin mRNA levels determined by a quantitative RT‐PCR method. *P < 0.05. a.u, arbitrary unit.
Figure 8
Figure 8
Lipid droplets in cardiomyocytes and tissue triglyceride levels: LETO versus OLETF. (A) Representative electron micrographs for lipid droplets (arrowheads) in the myocardium from LETO, OLETF treated with a vehicle, and OLETF treated with empagliflozin (Empa) that were subjected to a sham operation or coronary artery ligation (MI). Scale bar = 2 μm. Data for the percentage of total area of lipid droplets (B), number of lipid droplets per area (C), and size of lipid droplets (D) in six groups are shown. Ten images were taken from each heart, and data for five or six rats in each group were analyzed. (E) Myocardial triglyceride levels (μg/mg cardiac tissue) in the noninfarct myocardium. N = 9 in each group. *P < 0.05.

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