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

• Published in: Physiological reports Vol. 6; no. 12; pp. e13741 - n/a
• Main Authors: Mizuno, Masashi, Kuno, Atsushi, Yano, Toshiyuki, Miki, Takayuki, Oshima, Hiroto, Sato, Tatsuya, Nakata, Kei, Kimura, Yukishige, Tanno, Masaya, Miura, Tetsuji
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.06.2018; John Wiley and Sons Inc
• Subjects: Acute myocardial infarction; Animals; Antidiabetics; Autophagy; Autophagy - drug effects; Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; Blood Glucose - metabolism; Blood pressure; BNIP3 protein; Cardiac Muscle; Cardiomyocytes; Cardiovascular Conditions, Disorders and Treatments; Catalase; Cholesterol - blood; Congestive heart failure; Coronary artery; Coronary vessels; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; empagliflozin; Endocrine and Metabolic Conditons, Disorders and Treatments; Fatty acids; Glucosides - pharmacology; Glucosides - therapeutic use; Heart attacks; Heart failure; Ischemia; Laboratory animals; Lipids; Male; Microscopy, Electron; Mitochondria; Mitochondria, Heart - drug effects; Mitochondria, Heart - ultrastructure; Mitochondrial Proteins - metabolism; Mitochondrial Size - drug effects; Morphology; Mortality; Myocardial infarction; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocytes, Cardiac - ultrastructure; Original Research; Ostomy; Phagocytosis; Phosphorylation; Physiology; Rats, Inbred OLETF; Reactive Oxygen Species - metabolism; Regulatory Pathways; Rodents; SGLT2 inhibitor; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Studies; Superoxide dismutase; Triglycerides; Triglycerides - blood; Ultrastructure; Vacuoles; Vacuoles - drug effects; Veins & arteries; Ventricle; Japan; empagliflozin; diabetes mellitus; Acute myocardial infarction; SGLT2 inhibitor; mitochondria
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.13741

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. Empagliflozin, an SGLT2 inhibitor, normalized the size and number of mitochondria in diabetic hearts. In addition, this agent prevented diabetes‐induced excess reduction in mitochondrial size in the noninfarcted myocardium after myocardial infarction.