Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7115, USA.
Basic Res Cardiol. 2012 Jul;107(4):271. doi: 10.1007/s00395-012-0271-7. Epub 2012 May 31.
Although the murine late pregnant (LP) heart is speculated to be a better functioning heart during physiological conditions, the susceptibility of LP hearts to I/R injury is still unknown. The aims of this study were to investigate the cardiac vulnerability of LP rodents to ischemia/reperfusion (I/R) injury and to explore its underlying mechanisms. In vivo female rat hearts [non-pregnant (NP) or LP] or ex vivo Langendorff-perfused mouse hearts were subjected to I/R. The infarct size was approximately fourfold larger in LP animals compared with NP both in vivo and ex vivo. The heart functional recovery was extremely poor in LP mice compared with NP (~10% recovery in LP vs. 80% recovery in NP at the end of reperfusion, P < 0.01). Interestingly, the poor functional recovery and the larger infarct size in LP were partially restored one day post-partum and almost fully restored 1 week post-partum to their corresponding NP levels. Mitochondrial respiratory function and the threshold for opening of the mitochondrial permeability transition pore were significantly lower in LP compared with NP when they both were subjected to myocardial I/R injury [Respiratory control ratio = 1.9 ± 0.1 vs. 4.0 ± 0.5 in NP, P < 0.05; calcium retention capacity (CRC) = 167 ± 10 vs. 233 ± 18 nmol/mg protein in NP, P < 0.01]. Cardiac reactive oxygen species (ROS) generation, as well mitochondrial superoxide production, was approximately twofold higher in LP compared with NP following I/R. The phosphorylation levels of Akt, ERK1/2, and STAT3, but not GSK3β, were significantly reduced in the hearts from LP subjected to I/R. In conclusion, increased mitochondrial ROS generation, decreased CRC as well as impaired activation of Akt/ERK/STAT3 at reperfusion are the possible underlying mechanisms for higher vulnerability of LP hearts to I/R.
虽然人们推测，在生理条件下，鼠类妊娠晚期（late pregnant，LP）心脏的功能更好，但 LP 心脏对缺血/再灌注（ischemia/reperfusion，I/R）损伤的易感性仍不清楚。本研究旨在探讨 LP 啮齿动物心脏对 I/R 损伤的易损性，并探讨其潜在机制。将雌性大鼠（非妊娠（non-pregnant，NP）或 LP）心脏或 Langendorff 灌流的雄性小鼠心脏进行 I/R。体内和体外实验均显示，LP 动物的梗死面积比 NP 动物大约大 4 倍。LP 小鼠的心脏功能恢复极差，与 NP 相比，恢复率约为 10%（再灌注结束时 LP 为 10%，NP 为 80%，P < 0.01）。有趣的是，LP 心脏的这种较差的功能恢复和较大的梗死面积在产后第 1 天部分恢复，在产后第 1 周几乎完全恢复到相应的 NP 水平。当 LP 和 NP 都受到心肌 I/R 损伤时，LP 的线粒体呼吸功能和线粒体通透性转换孔（mitochondrial permeability transition pore，mPTP）开放的阈值明显低于 NP[呼吸控制比（Respiratory control ratio）= 1.9 ± 0.1 对 4.0 ± 0.5，NP，P < 0.05；钙保留能力（calcium retention capacity，CRC）= 167 ± 10 对 233 ± 18 nmol/mg 蛋白，NP，P < 0.01]。LP 心脏在 I/R 后产生的心脏活性氧（reactive oxygen species，ROS）和线粒体超氧化物的水平大约是 NP 的两倍。在 I/R 后，LP 心脏中 Akt、ERK1/2 和 STAT3 的磷酸化水平明显低于 NP，但 GSK3β 的磷酸化水平没有明显变化。总之，在再灌注时增加的线粒体 ROS 生成、减少的 CRC 以及 Akt/ERK/STAT3 激活受损，可能是 LP 心脏对 I/R 更易感性的潜在机制。
