Department of Kinesiology, Brody School of Medicine, East Carolina University, Greenville NC 27834, USA.
J Mol Cell Cardiol. 2012 May;52(5):1009-18. doi: 10.1016/j.yjmcc.2012.02.009. Epub 2012 Mar 3.
Mitochondria from diabetic hearts are sensitized to mitochondrial permeability transition pore (PTP) opening, which may be responsible for the increased propensity for cardiac injury in diabetic hearts. The purpose of this study was to determine if redox-dependent PTP opening contributes to augmented injury in diabetic hearts, and if compounds targeted at mitochondrial PTP, ROS, and calcium influx protected diabetic hearts from injury. Hearts from control or streptozotocin-induced diabetic rats were excised for either whole-heart or isolated mitochondria experiments. Myocardial glutathione content was oxidized in diabetic hearts when compared to control, and this translated to increased oxidation of the adenine nucleotide translocase in diabetic hearts. Diabetic mitochondria displayed significantly greater sensitivity to PTP opening than non-diabetic counterparts, which was reversed with the thiol-reducing agent dithiothreitol. The thiol-oxidant diamide increased calcium sensitivity in control, but not diabetic mitochondria. Diabetic animals treated with the mitochondria-targeted ROS suppressing peptide MTP-131 also showed improved resistance to PTP opening. In separate experiments hearts underwent ex vivo ischemia/reperfusion (IR). Diabetic hearts were more susceptible to IR injury, with infarct sizes of 60 ± 4% of the area-at-risk (vs. 46 ± 2% in non-diabetics; P<0.05). Administration of the PTP blocker NIM811 (5 μM), MTP-131 (1 nM) or the mitochondrial calcium uniporter blocker minocycline (1 μM) at the onset of reperfusion reduced infarct sizes in both control and diabetic hearts. These findings suggest that augmented susceptibility to injury in the diabetic heart is mediated by redox-dependent shifts in PTP opening, and that three novel mitochondria-targeted agents administered at reperfusion may be suitable adjuvant reperfusion therapies to attenuate injury in diabetic patients.
糖尿病心脏中的线粒体对线粒体通透性转换孔（PTP）开放敏感，这可能是糖尿病心脏中心肌损伤易感性增加的原因。本研究的目的是确定氧化还原依赖性 PTP 开放是否导致糖尿病心脏中损伤增加，以及针对线粒体 PTP、ROS 和钙流入的化合物是否能保护糖尿病心脏免受损伤。从对照或链脲佐菌素诱导的糖尿病大鼠中取出心脏进行全心或分离线粒体实验。与对照相比，糖尿病心脏中的心肌谷胱甘肽含量氧化，这导致糖尿病心脏中的腺嘌呤核苷酸转位酶氧化增加。与非糖尿病对照组相比，糖尿病线粒体对 PTP 开放的敏感性显著增加，而巯基还原剂二硫苏糖醇可逆转这种情况。硫醇氧化剂二酰胺增加了对照线粒体的钙敏感性，但对糖尿病线粒体没有影响。用靶向线粒体 ROS 的肽 MTP-131 治疗的糖尿病动物也显示出对 PTP 开放的改善抗性。在单独的实验中，心脏经历了离体缺血/再灌注（IR）。糖尿病心脏对 IR 损伤更敏感，梗塞面积为危险区面积的 60±4%（非糖尿病组为 46±2%；P<0.05）。在再灌注开始时给予 PTP 阻断剂 NIM811（5 μM）、MTP-131（1 nM）或线粒体钙单向转运体阻断剂米诺环素（1 μM）可减少对照和糖尿病心脏中的梗塞面积。这些发现表明，糖尿病心脏中损伤易感性增加是由氧化还原依赖性 PTP 开放转移介导的，并且在再灌注时给予三种新型靶向线粒体的药物可能是适合的辅助再灌注治疗方法，可减轻糖尿病患者的损伤。
