Genetic deletion or pharmacologic inhibition of histone deacetylase 6 protects the heart against ischaemia/reperfusion injury by limiting tumour necrosis factor alpha-induced mitochondrial injury in experimental diabetes.

Autor:	Baumgardt SL; Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53206, USA., Fang J; Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53206, USA., Fu X; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Chicago, IL 60611, USA.; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA.; Department of Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA., Liu Y; Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53206, USA., 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, IL 60611, USA., Chen L; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Chicago, IL 60611, USA.; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA.; Department of Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA., Mishra R; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Chicago, IL 60611, USA.; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA.; Department of Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA., Gunasekaran M; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Chicago, IL 60611, USA.; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA.; Department of Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA., Saha P; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Chicago, IL 60611, USA.; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA.; Department of Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA., Forbess JM; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Chicago, IL 60611, USA.; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA.; Department of Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA., Bosnjak ZJ; Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53206, USA.; Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53206, USA., Camara AKS; Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53206, USA., Kersten JR; Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53206, USA., Thorp EB; Department of Pathology, Feinberg School of Medicine, Northwestern University, 300 E. Superior Avenue, Chicago, IL 60611, USA.; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 300 E. Superior Avenue, Chicago, IL 60611, USA., Kaushal S; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Chicago, IL 60611, USA.; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA.; Department of Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA., Ge ZD; Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53206, USA.; Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Chicago, IL 60611, USA.; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA.; Department of Surgery, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA.; Department of Pathology, Feinberg School of Medicine, Northwestern University, 300 E. Superior Avenue, Chicago, IL 60611, USA.; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, 300 E. Superior Avenue, Chicago, IL 60611, USA.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2024 Oct 14; Vol. 120 (12), pp. 1456-1471.
DOI:	10.1093/cvr/cvae144
Abstrakt:	Aims: The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A (TubA), reduces myocardial ischaemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments the activity of HDAC6 and the generation of tumour necrosis factor alpha (TNF-α) and impairs mitochondrial complex I (mCI). Here, we examined how HDAC6 regulates TNF-α production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI. Methods and Results: HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNF-α, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of adenosine triphosphate. Importantly, genetic disruption of HDAC6 or TubA decreased TNF-α levels, mitochondrial fission, and myocardial mitochondrial nicotinamide adenine dinucleotide levels in ischaemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or TubA treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNF-α levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown. Conclusion: HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNF-α-induced mitochondrial injury in experimental diabetes. Competing Interests: Conflict of interest: none declared. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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