Dörner Andrea, Lynetskiy Oleg, Euler Gerhild, Landmesser Ulf, Schlüter Klaus-Dieter, Heger Jacqueline
Department of Cardiology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12200 Berlin, Germany.
DZHK, German Centre for Cardiovascular Research, Partner Site Berlin, 13347 Berlin, Germany.
Membranes (Basel). 2021 Oct 29;11(11):836. doi: 10.3390/membranes11110836.
Reperfusion is the only feasible therapy following myocardial infarction, but reperfusion has been shown to damage mitochondrial function and disrupt energy production in the heart. Adenine nucleotide translocase 1 (ANT1) facilitates the transfer of ADP/ATP across the inner mitochondrial membrane; therefore, we tested whether ANT1 exerts protective effects on mitochondrial function during ischemia/reperfusion (I/R). The hearts of wild-type (WT) and transgenic ANT1-overexpressing (ANT1-TG) rats were exposed to I/R injury using the standard Langendorff technique, after which mitochondrial function, hemodynamic parameters, infarct size, and components of the contractile apparatus were determined. ANT1-TG hearts expressed higher ANT protein levels, with reduced levels of oxidative 4-hydroxynonenal ANT modifications following I/R. ANT1-TG mitochondria isolated from I/R hearts displayed stable calcium retention capacity (CRC) and improved membrane potential stability compared with WT mitochondria. Mitochondria isolated from ANT1-TG hearts experienced less restricted oxygen consumption than WT mitochondria after I/R. Left ventricular diastolic pressure (Pdia) decreased in ANT1-TG hearts compared with WT hearts following I/R. Preserved diastolic function was accompanied by a decrease in the phospho-lamban (PLB)/sarcoplasmic reticulum calcium ATPase (SERCA2a) ratio in ANT1-TG hearts compared with that in WT hearts. In addition, the phosphorylated (P)-PLB/PLB ratio increased in ANT1-TG hearts after I/R but not in WT hearts, which indicated more effective calcium uptake into the sarcoplasmic reticulum in ANT1-TG hearts. In conclusion, ANT1-TG rat hearts coped more efficiently with I/R than WT rat hearts, which was reflected by preserved mitochondrial energy balance, diastolic function, and calcium dynamics after reperfusion.
再灌注是心肌梗死后唯一可行的治疗方法，但已证明再灌注会损害线粒体功能并扰乱心脏的能量产生。腺嘌呤核苷酸转位酶1（ANT1）促进ADP/ATP穿过线粒体内膜的转运；因此，我们测试了ANT1在缺血/再灌注（I/R）期间是否对线粒体功能发挥保护作用。使用标准的Langendorff技术使野生型（WT）和过表达ANT1的转基因（ANT1-TG）大鼠的心脏遭受I/R损伤，之后测定线粒体功能、血流动力学参数、梗死面积和收缩装置的组成成分。ANT1-TG心脏中ANT蛋白水平较高，I/R后氧化型4-羟基壬烯醛修饰的ANT水平降低。与WT线粒体相比，从I/R心脏分离的ANT1-TG线粒体表现出稳定的钙保留能力（CRC）和改善的膜电位稳定性。I/R后，从ANT1-TG心脏分离的线粒体比WT线粒体的氧消耗受限更少。与WT心脏相比，I/R后ANT1-TG心脏的左心室舒张压（Pdia）降低。与WT心脏相比，ANT1-TG心脏舒张功能的保留伴随着磷酸化受磷蛋白（PLB）/肌浆网钙ATP酶（SERCA2a）比值的降低。此外，I/R后ANT1-TG心脏中磷酸化（P）-PLB/PLB比值升高，但WT心脏中未升高，这表明ANT1-TG心脏中钙更有效地摄取到肌浆网中。总之，ANT1-TG大鼠心脏比WT大鼠心脏更有效地应对I/R，这体现在再灌注后线粒体能量平衡、舒张功能和钙动力学的保留上。
