Transgenic Overexpression of Adenine Nucleotide Translocase 1 Protects Ischemic Hearts Against Oxidative Stress

Overview

Journal J Mol Med (Berl)

Specialty General Medicine

Date 2016 Apr 16

PMID 27080394

Citations 18

Authors

Inga Klumpe

Konstantinos Savvatis

Dirk Westermann

Carsten Tschope

Ursula Rauch

Ulf Landmesser

Heinz-Peter Schultheiss

Andrea Dorner

Affiliations

Soon will be listed here.

Abstract

Unlabelled: Ischemia impairs the adenine nucleotide translocase (ANT), which transports ADP and ATP across the inner mitochondrial membrane. We investigated whether ANT1 overexpression has protective effects on ischemic hearts. Myocardial infarction was induced in wild-type (WT) and heart-specific ANT1-transgenic (ANT1-TG) rats, and hypoxia was set in isolated cardiomyocytes. ANT1 overexpression reduced the myocardial infarct area and increased the survival rate of infarcted rats. Reduced ANT1 expression and increased 4-hydroxynonenal modification of ANT paralleled to impaired ANT function in infarcted WT hearts. ANT1 overexpression improved ANT expression and function. This was accompanied by reduced mitochondrial cytochrome C release and caspase-3 activation. ANT1-TG hearts suffered less from oxidative stress, as shown by lower protein carbonylation and 4-hydroxynonenal modification of ANT. ANT1 overexpression also increased cell survival of hypoxic cardiomyocytes and attenuated reactive oxygen species (ROS) production. This was linked to higher stability of mitochondrial membrane potential and lower activity of ROS detoxifying catalase. ANT1-TG cardiomyocytes also showed higher resistance against H2O2 treatment, which was independent of catalase activity. In conclusion, ANT1 overexpression compensates impaired ANT activity under oxygen-restricted conditions. It reduces ROS production and oxidative stress, stabilizes mitochondrial integrity, and increases survival, making ANT1 a component in ROS management and heart protection during ischemia.

Key Messages: ANT1 overexpression reduces infarct size and increases survival after infarction. ANT1 overexpression compensates restricted ANT expression and function in infarcted hearts. Increased ANT1 expression enhances mitochondrial integrity. ANT1-overexpressing hearts reduce oxidative stress by decreasing ROS generation. ANT1 is a component in ROS management and heart protection.

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References

Halestrap A, Richardson A . The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol. 2014; 78:129-41. DOI: 10.1016/j.yjmcc.2014.08.018. View

Chen J, Bertrand H, Yu B . Inhibition of adenine nucleotide translocator by lipid peroxidation products. Free Radic Biol Med. 1995; 19(5):583-90. DOI: 10.1016/0891-5849(95)00066-7. View

Dorner A, Olesch M, Giessen S, Pauschinger M, Schultheiss H . Transcription of the adenine nucleotide translocase isoforms in various types of tissues in the rat. Biochim Biophys Acta. 1999; 1417(1):16-24. DOI: 10.1016/s0005-2736(98)00245-4. View

Jaganjac M, Cipak A, Schaur R, Zarkovic N . Pathophysiology of neutrophil-mediated extracellular redox reactions. Front Biosci (Landmark Ed). 2015; 21(4):839-55. DOI: 10.2741/4423. View

Eaton P, Li J, Hearse D, Shattock M . Formation of 4-hydroxy-2-nonenal-modified proteins in ischemic rat heart. Am J Physiol. 1999; 276(3):H935-43. DOI: 10.1152/ajpheart.1999.276.3.H935. View

Graham B, Waymire K, Cottrell B, Trounce I, Macgregor G, Wallace D . A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat Genet. 1997; 16(3):226-34. DOI: 10.1038/ng0797-226. View

Bittar N, Shug A, Folts J, Koke J . Ischemic-like change produced in canine heart by atractyloside: a chemical model. Recent Adv Stud Cardiac Struct Metab. 1976; 12:167-74. View

Winter J, Klumpe I, Heger J, Rauch U, Schultheiss H, Landmesser U . Adenine nucleotide translocase 1 overexpression protects cardiomyocytes against hypoxia via increased ERK1/2 and AKT activation. Cell Signal. 2015; 28(1):152-9. DOI: 10.1016/j.cellsig.2015.11.002. View

Koch M, Spillmann F, Dendorfer A, Westermann D, Altmann C, Sahabi M . Cardiac function and remodeling is attenuated in transgenic rats expressing the human kallikrein-1 gene after myocardial infarction. Eur J Pharmacol. 2006; 550(1-3):143-8. DOI: 10.1016/j.ejphar.2006.08.054. View

10.

Vieira H, Belzacq A, Haouzi D, Bernassola F, Cohen I, Jacotot E . The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal. Oncogene. 2001; 20(32):4305-16. DOI: 10.1038/sj.onc.1204575. View

11.

PELL S, Fayerweather W . Trends in the incidence of myocardial infarction and in associated mortality and morbidity in a large employed population, 1957-1983. N Engl J Med. 1985; 312(16):1005-11. DOI: 10.1056/NEJM198504183121601. View

12.

Duan J, Karmazyn M . Relationship between oxidative phosphorylation and adenine nucleotide translocase activity of two populations of cardiac mitochondria and mechanical recovery of ischemic hearts following reperfusion. Can J Physiol Pharmacol. 1989; 67(7):704-9. DOI: 10.1139/y89-114. View

13.

Tsutsui H, Ide T, Kinugawa S . Mitochondrial oxidative stress, DNA damage, and heart failure. Antioxid Redox Signal. 2006; 8(9-10):1737-44. DOI: 10.1089/ars.2006.8.1737. View

14.

Vyssokikh M, Katz A, Rueck A, Wuensch C, Dorner A, Zorov D . Adenine nucleotide translocator isoforms 1 and 2 are differently distributed in the mitochondrial inner membrane and have distinct affinities to cyclophilin D. Biochem J. 2001; 358(Pt 2):349-58. PMC: 1222067. DOI: 10.1042/0264-6021:3580349. View

15.

Narula J, Pandey P, Arbustini E, Haider N, Narula N, Kolodgie F . Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci U S A. 1999; 96(14):8144-9. PMC: 22202. DOI: 10.1073/pnas.96.14.8144. View

16.

Chinnaiyan A . The apoptosome: heart and soul of the cell death machine. Neoplasia. 2000; 1(1):5-15. PMC: 1716059. DOI: 10.1038/sj.neo.7900003. View

17.

Nickel A, Kohlhaas M, Maack C . Mitochondrial reactive oxygen species production and elimination. J Mol Cell Cardiol. 2014; 73:26-33. DOI: 10.1016/j.yjmcc.2014.03.011. View

18.

Esposito L, Melov S, Panov A, Cottrell B, Wallace D . Mitochondrial disease in mouse results in increased oxidative stress. Proc Natl Acad Sci U S A. 1999; 96(9):4820-5. PMC: 21775. DOI: 10.1073/pnas.96.9.4820. View

19.

Koch M, Savvatis K, Scheeler M, Dhayat S, Bonaventura K, Pohl T . Immunosuppression with an interleukin-2 fusion protein leads to improved LV function in experimental ischemic cardiomyopathy. Int Immunopharmacol. 2009; 10(2):207-12. DOI: 10.1016/j.intimp.2009.11.001. View

20.

Belzacq A, Vieira H, Kroemer G, Brenner C . The adenine nucleotide translocator in apoptosis. Biochimie. 2002; 84(2-3):167-76. DOI: 10.1016/s0300-9084(02)01366-4. View