Effect of fetal hypoxia on heart susceptibility to ischemia and reperfusion injury in the adult rat.
OBJECTIVE
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.


METHODS
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)).


RESULTS
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.


CONCLUSIONS
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.
Li
Guohu
G
Center for Perinatal Biology, Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, California, USA.
Xiao
Yuhui
Y
Estrella
Jaymie L
JL
Ducsay
Charles A
CA
Gilbert
Raymond D
RD
Zhang
Lubo
L
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D005260:Female; D005311:Fetal Hypoxia / Q000150:complications*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000032:analysis; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000032:analysis; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis; D006352:Heart Ventricles / Q000737:chemistry; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology; D017202:Myocardial Ischemia / Q000209:etiology*; D015428:Myocardial Reperfusion Injury / Q000209:etiology*; D019001:Nitric Oxide Synthase / Q000032:analysis; D052250:Nitric Oxide Synthase Type III; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000032:analysis; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis; D016277:Ventricular Function, Left
D018840:HSP70 Heat-Shock Proteins; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs