Neckář Jan, Svatoňová Anna, Weissová Romana, Drahota Zdeněk, Zajíčková Pavlína, Brabcová Iveta, Kolář David, Alánová Petra, Vašinová Jana, Šilhavý Jan, Hlaváčková Markéta, Tauchmannová Kateřina, Milerová Marie, Ošťádal Bohuslav, Červenka Luděk, Žurmanová Jitka, Kalous Martin, Nováková Olga, Novotný Jiří, Pravenec Michal, Kolář František
Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic
Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
Clin Sci (Lond). 2017 May 1;131(9):865-881. doi: 10.1042/CS20170083. Epub 2017 Mar 14.
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-mt strain, 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% O, 3 weeks) or kept at room air as normoxic controls. In the left ventricular mitochondria, respiration and cytochrome oxidase (COX) activity were measured using an Oxygraph-2k and the sensitivity of MPTP opening was assessed spectrophotometrically as Ca-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-mt strains, respectively. CNH significantly decreased myocardial infarction to 46±3% in SHR. In hypoxic SHR-mt strain, 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-mt strain 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.
线粒体在适应慢性低氧所赋予的改善心脏缺血耐受性方面发挥着重要作用。在本研究中，我们分析了持续常压低氧（CNH）对线粒体功能的影响，包括线粒体通透性转换孔（MPTP）开放的敏感性，以及自发性高血压大鼠（SHR）和同基因SHR-mt品系心脏的梗死面积（IS）。SHR-mt品系的特征是用缺血耐受性更强的棕色挪威（BN）品系的线粒体基因组选择性替换SHR的线粒体基因组。将大鼠置于CNH环境（10%氧气，3周）或置于常氧环境作为常氧对照。在左心室线粒体中，使用Oxygraph-2k测量呼吸和细胞色素氧化酶（COX）活性，并通过分光光度法评估MPTP开放的敏感性，即钙诱导的肿胀。对接受20分钟冠状动脉闭塞和3小时再灌注的麻醉开胸大鼠进行心肌梗死分析。在常氧SHR和SHR-mt品系中，梗死面积分别达到危险区域面积的68±3.0%和65±5%。CNH显著降低了SHR的心肌梗死面积至46±3%。在低氧SHR-mt品系中，梗死面积达到33±2%，与低氧SHR相比显著更小。从两个品系的低氧心脏中分离出的线粒体具有增强的去污剂刺激的COX活性，并且对MPTP开放的敏感性较低。与低氧SHR相比，低氧SHR-mt品系的最大肿胀率显著更低，并且在所有实验组中与心肌梗死呈正相关。总之，SHR的线粒体基因组通过影响线粒体能量代谢和MPTP开放敏感性来调节适应CNH对梗死面积的限制作用。
