A gene therapy targeting medium-chain acyl-CoA dehydrogenase (MCAD) did not protect against diabetes-induced cardiac pathology.

Autor: Weeks KL; Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, 3010, Australia.; Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, 3010, Australia.; Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC, 3800, Australia., Kiriazis H; Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, 3010, Australia.; Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia., Wadley GD; Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Burwood, VIC, 3125, Australia., Masterman EI; Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia., Sergienko NM; Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC, 3800, Australia.; Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia., Raaijmakers AJA; Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, 3010, Australia., Trewin AJ; Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, 3010, Australia., Harmawan CA; Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia., Yildiz GS; Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia., Liu Y; Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia., Drew BG; Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, 3010, Australia.; Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC, 3800, Australia.; Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia., Gregorevic P; Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, 3010, Australia.; Centre for Muscle Research, University of Melbourne, Parkville, VIC, 3010, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia.; Department of Neurology, University of Washington School of Medicine, Seattle, WA, 98195, USA., Delbridge LMD; Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, 3010, Australia., McMullen JR; Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, 3010, Australia.; Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC, 3800, Australia.; Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia.; Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC, 3086, Australia., Bernardo BC; Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC, 3800, Australia. bianca.bernardo@baker.edu.au.; Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia. bianca.bernardo@baker.edu.au.; Department of Paediatrics, University of Melbourne, Parkville, VIC, 3010, Australia. bianca.bernardo@baker.edu.au.
Jazyk: angličtina
Zdroj: Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2024 Jan; Vol. 102 (1), pp. 95-111. Date of Electronic Publication: 2023 Nov 21.
DOI: 10.1007/s00109-023-02397-2
Abstrakt: Diabetic cardiomyopathy describes heart disease in patients with diabetes who have no other cardiac conditions but have a higher risk of developing heart failure. Specific therapies to treat the diabetic heart are limited. A key mechanism involved in the progression of diabetic cardiomyopathy is dysregulation of cardiac energy metabolism. The aim of this study was to determine if increasing the expression of medium-chain acyl-coenzyme A dehydrogenase (MCAD; encoded by Acadm), a key regulator of fatty acid oxidation, could improve the function of the diabetic heart. Male mice were administered streptozotocin to induce diabetes, which led to diastolic dysfunction 8 weeks post-injection. Mice then received cardiac-selective adeno-associated viral vectors encoding MCAD (rAAV6:MCAD) or control AAV and were followed for 8 weeks. In the non-diabetic heart, rAAV6:MCAD increased MCAD expression (mRNA and protein) and increased Acadl and Acadvl, but an increase in MCAD enzyme activity was not detectable. rAAV6:MCAD delivery in the diabetic heart increased MCAD mRNA expression but did not significantly increase protein, activity, or improve diabetes-induced cardiac pathology or molecular metabolic and lipid markers. The uptake of AAV viral vectors was reduced in the diabetic versus non-diabetic heart, which may have implications for the translation of AAV therapies into the clinic. KEY MESSAGES: The effects of increasing MCAD in the diabetic heart are unknown. Delivery of rAAV6:MCAD increased MCAD mRNA and protein, but not enzyme activity, in the non-diabetic heart. Independent of MCAD enzyme activity, rAAV6:MCAD increased Acadl and Acadvl in the non-diabetic heart. Increasing MCAD cardiac gene expression alone was not sufficient to protect against diabetes-induced cardiac pathology. AAV transduction efficiency was reduced in the diabetic heart, which has clinical implications.
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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