title: Selective replacement of mitochondrial DNA increases the cardioprotective effect of chronic continuous hypoxia in spontaneously hypertensive rats.
abstract: Mitochondria play an essential role in improved cardiac ischaemic tolerance conferred by adaptation to chronic hypoxia. In the present study, we analysed the effects of continuous normobaric hypoxia (CNH) on mitochondrial functions, including the sensitivity of the mitochondrial permeability transition pore (MPTP) to opening, and infarct size (IS) in hearts of spontaneously hypertensive rats (SHR) and the conplastic SHR-mtBNstrain, characterized by the selective replacement of the mitochondrial genome of SHR with that of the more ischaemia-resistant brown Norway (BN) strain. Rats were adapted to CNH (10% O2, 3 weeks) or kept at room air as normoxic controls. In the left ventricular mitochondria, respiration and cytochromecoxidase (COX) activity were measured using an Oxygraph-2k and the sensitivity of MPTP opening was assessed spectrophotometrically as Ca2+-induced swelling. Myocardial infarction was analysed in anaesthetized open-chest rats subjected to 20 min of coronary artery occlusion and 3 h of reperfusion. The IS reached 68±3.0% and 65±5% of the area at risk in normoxic SHR and SHR-mtBNstrains, respectively. CNH significantly decreased myocardial infarction to 46±3% in SHR. In hypoxic SHR-mtBNstrain, IS reached 33±2% and was significantly smaller compared with hypoxic SHR. Mitochondria isolated from hypoxic hearts of both strains had increased detergent-stimulated COX activity and were less sensitive to MPTP opening. The maximum swelling rate was significantly lower in hypoxic SHR-mtBNstrain compared with hypoxic SHR, and positively correlated with myocardial infarction in all experimental groups. In conclusion, the mitochondrial genome of SHR modulates the IS-limiting effect of adaptation to CNH by affecting mitochondrial energetics and MPTP sensitivity to opening.
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic jan.neckar@fgu.cas.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Neckář
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Svatoňová
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.|Department of Cell Biology, Faculty of Science, Charles Univesity, Viničná 7, Prague, 12800, Czech Republic.
authors.forename: Romana
authors.initials: R
authors.lastname: Weissová
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Drahota
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Pavlína
authors.initials: P
authors.lastname: Zajíčková
authors.affiliation: Deparment of Physiology, Faculty of Science, Charles University, Viničná 7, Prague, 12800, Czech Republic.
authors.forename: Iveta
authors.initials: I
authors.lastname: Brabcová
authors.affiliation: Deparment of Physiology, Faculty of Science, Charles University, Viničná 7, Prague, 12800, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Kolář
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Alánová
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Vašinová
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Šilhavý
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Markéta
authors.initials: M
authors.lastname: Hlaváčková
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Tauchmannová
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Milerová
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Bohuslav
authors.initials: B
authors.lastname: Ošťádal
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Vídeňská 1958/9, Prague, 14021, Czech Republic.
authors.forename: Luděk
authors.initials: L
authors.lastname: Červenka
authors.affiliation: Deparment of Physiology, Faculty of Science, Charles University, Viničná 7, Prague, 12800, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Žurmanová
authors.affiliation: Department of Cell Biology, Faculty of Science, Charles Univesity, Viničná 7, Prague, 12800, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Kalous
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.|Deparment of Physiology, Faculty of Science, Charles University, Viničná 7, Prague, 12800, Czech Republic.
authors.forename: Olga
authors.initials: O
authors.lastname: Nováková
authors.affiliation: Deparment of Physiology, Faculty of Science, Charles University, Viničná 7, Prague, 12800, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Novotný
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
authors.forename: František
authors.initials: F
authors.lastname: Kolář
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002908:Chronic Disease; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D054629:Genome, Mitochondrial / Q000235:genetics; D000860:Hypoxia; D008297:Male; D008929:Mitochondria, Heart / Q000235:genetics* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR; D055647:Rats, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004272:DNA, Mitochondrial; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D003576:Electron Transport Complex IV
keywords: chronic hypoxia; heart; hypertension; ischaemia–reperfusion injury; mitochondrial genome; mitochondrial permeability transition pore