Department of Anesthesiology, Stony Brook University School of Medicine, NY 11794, USA.
Acta Anaesthesiol Scand. 2011 May;55(5):622-30. doi: 10.1111/j.1399-6576.2011.02421.x.
Inhibiting mitochondrial permeability transition pore (mPTP) opening is a key protection of the myocardium from ischemia/reperfusion (I/R) injury. Here, we investigated age-associated differences in the ability of cyclosporine A (CsA) to protect the heart and to modulate mPTP opening during I/R injury in vivo and its opening induced by reactive oxygen species (ROS) in vitro.
Fischer 344 male rats were assigned from their respective age groups, young or old groups, to (1) I/R or (2) I/R+CsA. All animals were subjected to 30 min of ischemia following 120 min of reperfusion to determine myocardial infarct size in vivo. To measure mPTP opening in vivo, left ventricular tissues were collected 10 min after reperfusion and nicotinamide adenine dinucleotide (NAD(+)) levels were measured. In parallel experiments, rat ventricular myocytes were prepared from young and old hearts, loaded with tetramethylrhodamine ethylester and then subjected to oxidative stress in the presence or absence of CsA, and the mPTP opening time was measured using laser scanning confocal microscopy.
CsA reduced myocardial infarct size in young I/R rats. Whereas CsA failed to significantly affect myocardial infarct size in old I/R rats, NAD(+) levels were better preserved in young CsA-treated rats, but this relative improvement was not observed in old rats. CsA also significantly prolonged the time necessary to induce mPTP opening in young cardiomyocytes, but not in cardiomyocytes isolated from the old rats.
mPTP regulation is dysfunctional in the aged myocardium and this could account for loss of cardioprotection with aging.
抑制线粒体通透性转换孔（mPTP）的开放是心肌免受缺血/再灌注（I/R）损伤的关键保护机制。在这里，我们研究了环孢素 A（CsA）在体内 I/R 损伤期间保护心脏和调节 mPTP 开放的能力以及其在体外由活性氧（ROS）诱导的 mPTP 开放的能力随年龄的变化差异。
将 Fischer 344 雄性大鼠从各自的年龄组（年轻组或老年组）中分配，分为（1）I/R 或（2）I/R+CsA 组。所有动物均接受 30 分钟缺血，然后再进行 120 分钟再灌注，以确定体内心肌梗死面积。为了测量体内 mPTP 的开放，在再灌注 10 分钟后收集左心室组织并测量烟酰胺腺嘌呤二核苷酸（NAD(+））水平。在平行实验中，从年轻和老年心脏中制备大鼠心室肌细胞，用四甲基罗丹明乙酯负载，然后在存在或不存在 CsA 的情况下进行氧化应激，使用激光扫描共聚焦显微镜测量 mPTP 的开放时间。
CsA 减少了年轻 I/R 大鼠的心肌梗死面积。然而，CsA 对老年 I/R 大鼠的心肌梗死面积没有显著影响，但在年轻 CsA 治疗的大鼠中 NAD(+)水平更好地得到了保留，但在老年大鼠中没有观察到这种相对改善。CsA 还显著延长了诱导年轻心肌细胞 mPTP 开放所需的时间，但对分离自老年大鼠的心肌细胞没有影响。
mPTP 的调节在老年心肌中失调，这可能是随着年龄的增长而导致心脏保护作用丧失的原因。
