Li Guohu, Xiao Yuhui, Estrella Jaymie L, Ducsay Charles A, Gilbert Raymond D, Zhang Lubo
Center for Perinatal Biology, Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, California, USA.
J Soc Gynecol Investig. 2003 Jul;10(5):265-74. doi: 10.1016/s1071-5576(03)00074-1.
Epidemiologic studies showed an association between adverse intrauterine environment and ischemic heart disease in the adult. We tested the hypothesis that prenatal hypoxia increased the susceptibility of adult heart to ischemia-reperfusion (I-R) injury.
Time-dated pregnant rats were divided between normoxic and hypoxic (10.5% oxygen from day 15 to 21) groups. Hearts of 6-month-old male progeny were studied using Langendorff preparation and were subjected to two protocols of I-R: 10 minutes of ischemia and 3 hours of reperfusion (I-R(10)) or 25 minutes of ischemia and 3 hours of reperfusion (I-R(25)).
Prenatal hypoxia did not change basal left ventricular (LV) function. I-R(10) produced myocardial stunning and a transient decrease in LV function in control hearts but caused myocardial infarction and a persistent decrease in postischemic recovery of LV function in hypoxic hearts. I-R(25) caused myocardial infarction in both control and hypoxic hearts, which was significantly higher in hypoxic hearts. The postischemic recovery of LV function was significantly reduced in hypoxic hearts. I-R(25)-induced activation of caspase-3 and apoptosis in the left ventricle were significantly higher in hypoxic than control hearts. There was a significant decrease in LV heat shock protein 70 and endothelial nitric oxide synthase levels in hypoxic hearts. Prenatal hypoxia did not change beta(1)-adrenoreceptor levels but significantly increased beta(2)-adrenoreceptor in the left ventricle. In addition, it increased G(s)alpha but decreased G(i)alpha.
Prenatal chronic hypoxia increases the susceptibility of adult heart to I-R injury. Several possible mechanisms may be involved, including an increase in beta(2)-adrenoreceptor and the G(s)alpha/G(i)alpha ratio, and a decrease in heat shock protein 70 and endothelial nitric oxide synthase in the left ventricle.
流行病学研究表明，不良的子宫内环境与成年人缺血性心脏病之间存在关联。我们检验了产前缺氧会增加成年心脏对缺血再灌注（I-R）损伤易感性的假说。
将处于特定孕期的孕鼠分为常氧组和缺氧组（从第15天至21天给予10.5%的氧气）。对6月龄雄性子代的心脏采用Langendorff灌流法进行研究，并使其经历两种I-R方案：10分钟缺血和3小时再灌注（I-R(10)）或25分钟缺血和3小时再灌注（I-R(25)）。
产前缺氧并未改变基础左心室（LV）功能。I-R(10)在对照心脏中导致心肌顿抑和LV功能短暂下降，但在缺氧心脏中却引起心肌梗死以及缺血后LV功能恢复的持续下降。I-R(25)在对照和缺氧心脏中均导致心肌梗死，且在缺氧心脏中梗死程度显著更高。缺氧心脏中缺血后LV功能的恢复显著降低。与对照心脏相比，I-R(25)诱导的缺氧心脏左心室中半胱天冬酶-3激活和细胞凋亡显著更高。缺氧心脏中LV热休克蛋白70和内皮型一氧化氮合酶水平显著降低。产前缺氧未改变β1-肾上腺素能受体水平，但显著增加了左心室中的β2-肾上腺素能受体。此外，它增加了Gsα但降低了Giα。
产前慢性缺氧增加了成年心脏对I-R损伤的易感性。可能涉及多种机制，包括β₂-肾上腺素能受体及Gsα/Giα比值增加，以及左心室热休克蛋白70和内皮型一氧化氮合酶减少。
