Koentges Christoph, Pfeil Katharina, Meyer-Steenbuck Maximilian, Lother Achim, Hoffmann Michael M, Odening Katja E, Hein Lutz, Bode Christoph, Bugger Heiko
a Division of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany.
b Institute of Experimental and Clinical Pharmacology, and Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany.
Can J Physiol Pharmacol. 2016 Jan;94(1):72-80. doi: 10.1139/cjpp-2015-0152. Epub 2015 Jul 19.
Lack of the mitochondrial deacetylase sirtuin 3 (SIRT3) impairs mitochondrial function and increases the susceptibility to induction of the mitochondrial permeability transition pore. Because these alterations contribute to myocardial ischemia-reperfusion (IR) injury, we hypothesized that SIRT3 deficiency may increase cardiac injury following myocardial IR. Hearts of 10-week-old mice were perfused in the isolated working mode and subjected to 17.5 min of global no-flow ischemia, followed by 30 min of reperfusion. Measurements before ischemia revealed a decrease in cardiac power (-20%) and rate pressure product (-15%) in SIRT3(-/-) mice. Mitochondrial state 3 respiration (-15%), ATP synthesis (-39%), and ATP/O ratios (-29%) were decreased in hearts of SIRT3(-/-) mice. However, percent recovery of cardiac power (WT 94% ± 9%; SIRT3(-/-) 89% ± 9%) and rate pressure product (WT 89% ± 16%; SIRT3(-/-) 96% ± 3%) following IR was similar in both groups. Myocardial infarct size was not increased in SIRT3(-/-) mice following permanent ligation of the left anterior descending coronary artery (LAD). Left ventricular pressure and dP/dtmax, and mitochondrial respiration and ATP synthesis were not different between groups following LAD ligation. Thus, despite pre-existing defects in cardiac function and mitochondrial respiratory capacity in SIRT3(-/-) mice, SIRT3 deficiency does not additionally impair cardiac function following IR or following myocardial infarction.
线粒体去乙酰化酶沉默调节蛋白3（SIRT3）的缺失会损害线粒体功能，并增加线粒体通透性转换孔诱导的易感性。由于这些改变会导致心肌缺血再灌注（IR）损伤，我们推测SIRT3缺乏可能会增加心肌IR后的心脏损伤。对10周龄小鼠的心脏进行离体工作模式灌注，使其经历17.5分钟的全心无血流缺血，随后再灌注30分钟。缺血前的测量显示，SIRT3基因敲除（-/-）小鼠的心脏功率降低了20%，心率血压乘积降低了15%。SIRT3（-/-）小鼠心脏中的线粒体状态3呼吸（降低15%）、ATP合成（降低39%）和ATP/O比值（降低29%）均下降。然而，两组在IR后的心脏功率恢复百分比（野生型94%±9%；SIRT3（-/-）89%±9%）和心率血压乘积恢复百分比（野生型89%±16%；SIRT3（-/-）96%±3%）相似。在永久性结扎左冠状动脉前降支（LAD）后，SIRT3（-/-）小鼠的心肌梗死面积并未增加。LAD结扎后，两组之间的左心室压力和dP/dtmax以及线粒体呼吸和ATP合成没有差异。因此，尽管SIRT3（-/-）小鼠预先存在心脏功能和线粒体呼吸能力缺陷，但SIRT3缺乏在IR或心肌梗死后并不会额外损害心脏功能。
