D Laurent1, J E Mathew1, M Mitry1, M Taft1, A Force1, J G Edwards2. 1. Department of Physiology, New York Medical College, Valhalla, NY, USA. 2. Department of Physiology, New York Medical College, Valhalla, NY, USA j_edwards@nymc.edu.
Abstract
AIMS: Alcoholic cardiomyopathy (ACM) presents as decreased myocardial contractility, arrhythmias and secondary non-ischemic dilated cardiomyopathy leading to heart failure. Mitochondrial dysfunction is known to have a significant role in the development and complications of ACM. This study investigated if chronic ethanol feeding promoted myocardial mitochondrial topoisomerase dysfunction as one underlying cause of mitochondrial DNA (mtDNA) damage and mitochondrial dysfunction in ACM. METHODS: The impact of chronic ethanol exposure on the myocardial mitochondria was examined in both neonatal cardiomyocytes using 50 mM ethanol for 6 days and in rats assigned to control or ethanol feeding groups for 4 months. RESULTS: Chronic ethanol feeding led to significant (P < 0.05) decreases in M-mode Fractional Shortening, ejection fraction, and the cardiac output index as well as increases in Tau. Ethanol feeding promoted mitochondrial dysfunction as evidenced by significantly decreased left ventricle cytochrome oxidase activity and decreases in mitochondrial protein content. Both in rats and in cultured cardiomyocytes, chronic ethanol presentation significantly increased mtDNA damage. Using isolated myocardial mitochondria, both mitochondrial topoisomerase-dependent DNA cleavage and DNA relaxation were significantly altered by ethanol feeding. CONCLUSION: Chronic ethanol feeding compromised cardiovascular and mitochondrial function as a result of a decline in mtDNA integrity that was in part the consequence of mitochondrial topoisomerase dysfunction. Understanding the regulation of the mitochondrial topoisomerases is critical for protection of mtDNA, not only for the management of alcoholic cardiomyopathy, but also for the many other clinical treatments that targets the topoisomerases in the alcoholic patient.
AIMS: Alcoholic cardiomyopathy (ACM) presents as decreased myocardial contractility, arrhythmias and secondary non-ischemic dilated cardiomyopathy leading to heart failure. Mitochondrial dysfunction is known to have a significant role in the development and complications of ACM. This study investigated if chronic ethanol feeding promoted myocardial mitochondrial topoisomerase dysfunction as one underlying cause of mitochondrial DNA (mtDNA) damage and mitochondrial dysfunction in ACM. METHODS: The impact of chronic ethanol exposure on the myocardial mitochondria was examined in both neonatal cardiomyocytes using 50 mM ethanol for 6 days and in rats assigned to control or ethanol feeding groups for 4 months. RESULTS: Chronic ethanol feeding led to significant (P < 0.05) decreases in M-mode Fractional Shortening, ejection fraction, and the cardiac output index as well as increases in Tau. Ethanol feeding promoted mitochondrial dysfunction as evidenced by significantly decreased left ventricle cytochrome oxidase activity and decreases in mitochondrial protein content. Both in rats and in cultured cardiomyocytes, chronic ethanol presentation significantly increased mtDNA damage. Using isolated myocardial mitochondria, both mitochondrial topoisomerase-dependent DNA cleavage and DNA relaxation were significantly altered by ethanol feeding. CONCLUSION: Chronic ethanol feeding compromised cardiovascular and mitochondrial function as a result of a decline in mtDNA integrity that was in part the consequence of mitochondrial topoisomerase dysfunction. Understanding the regulation of the mitochondrial topoisomerases is critical for protection of mtDNA, not only for the management of alcoholic cardiomyopathy, but also for the many other clinical treatments that targets the topoisomerases in the alcoholic patient.
Authors: Alan Cahill; Carol C Cunningham; Masayuki Adachi; Hiromasa Ishii; Shannon M Bailey; Bernard Fromenty; Adrian Davies Journal: Alcohol Clin Exp Res Date: 2002-06 Impact factor: 3.455
Authors: Cristina Ugalde; Ralf H Triepels; Marieke J H Coenen; Lambert P van den Heuvel; Roel Smeets; Johanna Uusimaa; Paz Briones; Jaume Campistol; Kari Majamaa; Jan A M Smeitink; Leo G J Nijtmans Journal: Ann Neurol Date: 2003-11 Impact factor: 10.422
Authors: Paul S Pagel; John G Krolikowski; Franz Kehl; Boris Mraovic; Judy R Kersten; David C Warltier Journal: Anesth Analg Date: 2002-04 Impact factor: 5.108
Authors: Christopher T Sempos; Jürgen Rehm; Tiejian Wu; Carlos J Crespo; Maurizio Trevisan Journal: Alcohol Clin Exp Res Date: 2003-01 Impact factor: 3.455
Authors: Verónica Eisner; Ryan R Cupo; Erhe Gao; György Csordás; William S Slovinsky; Melanie Paillard; Lan Cheng; Jessica Ibetti; S R Wayne Chen; J Kurt Chuprun; Jan B Hoek; Walter J Koch; György Hajnóczky Journal: Proc Natl Acad Sci U S A Date: 2017-01-17 Impact factor: 11.205
Authors: Maria A Mitry; Dimitri Laurent; Britny L Keith; Elizabeth Sira; Carol A Eisenberg; Leonard M Eisenberg; Sachindra Joshi; Sachin Gupte; John G Edwards Journal: Am J Physiol Cell Physiol Date: 2020-01-08 Impact factor: 4.249