Augmentation of Histone Deacetylase 6 Activity Impairs Mitochondrial Respiratory Complex I in Ischemic/Reperfused Diabetic Hearts.

Autor:	Baumgardt SL; Departments of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53206., Fang J; Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53206., Fu X; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Departments of Pediatrics and Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, Illinois 60611., Liu Y; Departments of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53206., Xia Z; Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province, The People's Republic of China., Zhao M; The Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, 300 E. Superior Avenue, Chicago, Illinois 60611., Chen L; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Departments of Pediatrics and Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, Illinois 60611., Mishra R; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Departments of Pediatrics and Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, Illinois 60611., Gunasekaran M; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Departments of Pediatrics and Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, Illinois 60611., Saha P; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Departments of Pediatrics and Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, Illinois 60611., Forbess JM; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Departments of Pediatrics and Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, Illinois 60611., Bosnjak ZJ; Departments of Medicine and Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53206., Camara AK; Departments of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53206., Kersten JR; Departments of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53206., Thorp E; Departments of Pathology and Pediatrics, Feinberg School of Medicine, Northwestern University, 300 E. Superior Avenue, Chicago, Illinois 60611., Kaushal S; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Departments of Pediatrics and Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, Illinois 60611., Ge ZD; Departments of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53206.; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Departments of Pediatrics and Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, Illinois 60611.; Departments of Pathology and Pediatrics, Feinberg School of Medicine, Northwestern University, 300 E. Superior Avenue, Chicago, Illinois 60611.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Feb 22. Date of Electronic Publication: 2023 Feb 22.
DOI:	10.1101/2023.02.21.529462
Abstrakt:	Background: Diabetes augments activity of histone deacetylase 6 (HDAC6) and generation of tumor necrosis factor α (TNFα) and impairs the physiological function of mitochondrial complex I (mCI) which oxidizes reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide to sustain the tricarboxylic acid cycle and β-oxidation. Here we examined how HDAC6 regulates TNFα production, mCI activity, mitochondrial morphology and NADH levels, and cardiac function in ischemic/reperfused diabetic hearts. Methods: HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent myocardial ischemia/reperfusion injury in vivo or ex vivo in a Langendorff-perfused system. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. We compared the activities of HDAC6 and mCI, TNFα and mitochondrial NADH levels, mitochondrial morphology, myocardial infarct size, and cardiac function between groups. Results: Myocardial ischemia/reperfusion injury and diabetes synergistically augmented myocardial HDCA6 activity, myocardial TNFα levels, and mitochondrial fission and inhibited mCI activity. Interestingly, neutralization of TNFα with an anti-TNFα monoclonal antibody augmented myocardial mCI activity. Importantly, genetic disruption or inhibition of HDAC6 with tubastatin A decreased TNFα levels, mitochondrial fission, and myocardial mitochondrial NADH levels in ischemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and ameliorated cardiac dysfunction. In H9c2 cardiomyocytes cultured in high glucose, hypoxia/reoxygenation augmented HDAC6 activity and TNFα levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown. Conclusions: Augmenting HDAC6 activity inhibits mCI activity by increasing TNFα levels in ischemic/reperfused diabetic hearts. The HDAC6 inhibitor, tubastatin A, has high therapeutic potential for acute myocardial infarction in diabetes. Competing Interests: Conflict of Interest The authors declared no conflict of interest.
Databáze:	MEDLINE
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