Maternal treatment with agonistic autoantibodies against type-1 angiotensin II receptor in late pregnancy increases apoptosis of myocardial cells and myocardial susceptibility to ischemia-reperfusion injury in offspring rats

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Abstract

Epidemiological studies have demonstrated that offspring born to mothers preeclampsia (PE) are at increased risk for developing cardiovascular diseases after birth, but the underlying mechanism is unknown. Angiotensin II receptor type 1 autoantibody (AT1-AA), an agonist acting via activation of the AT1 receptor, is believed to be involved in the pathogenesis of both PE and fetal growth restriction. The aim of the present study was to confirm the hypothesis that prenatal AT1-AA exposure increases the heart susceptibility to ischemia/reperfusion injury (IRI) in the offspring in an AT1-AA-induced animal model of PE, and determine whether or not the increase of maternal AT1-AA level is a factor contributing to sustained abnormalities of the heart structure during infancy. The hearts of 45-day-old offspring rats were studied using Langendorff preparation to determine the susceptibility of the heart to IRI. The results showed that the body weight of the maternal rats was not significantly different between the study and control groups, but the body weight of their offspring in AT1-AA group was decreased slightly at day 21 of gestational age, and at day 3 after birth. Although the heart weight index was not significantly affected at all ages examined, AT1-AA significantly increased the size of myocardial cells of the left ventricle (LV) at the age of 45 days. AT1-AA gained access to fetal circulation via the placenta and induced apoptosis of fetal myocardial cells. AT1-AA also significantly delayed recovery from IRI and affected the LV function of 45-day-old offspring. This was associated with a significant increase in IRI-induced LV myocardial infarct size. These results suggest that AT1-AA induced abnormal apoptosis of fetal myocardial cells during the fetal period and increased the cardiac susceptibility to IRI in adult offspring. © 2013 Jin et al.

Figures

  • Table 1. Maternal and fetal characteristics.
  • Figure 1. Effect of prenatal AT1-AA exposure on LV crosssectional area of myocardial cells. Hearts were obtained from 45-day-old rats exposed to either saline or AT1-AA before birth from day 13 and 14 of gestational age. (A) Hematoxylin and eosin (H&E)-stained histological sections of hearts (bar, 3 mm); (B) Light-microscopic (400×) examination of cardiac tissue with H&E stained (bar, 100 µm); (C) The cross-sectional area (CSA) of myocardial cells in the left ventricular wall. Data are mean ± SD. *P<0.05, AT1-AA vs control, n=7–8.
  • Table 2. The effect of prenatal AT1-AA exposure on postnatal body and heart weight.
  • Figure 3. TUNEL assay of cardiac tissue obtained from fetal rats of 21 days gestational age exposed to either saline (A) or AT1-AA (B) before birth from day 13 and 14 of gestational age (200×, bar, 50 µm) . TUNEL-positive FRMCs showing shrunken cytoplasm, pycnotic nuclei, and/or apoptotic bodies increased. The percentage of TUNEL-positive myocardiac cells of each treatment is presented as the mean ± SD. C: Quantification of apoptotic cell death. *P<0.05, **P<0.01 vs. control.
  • Figure 2. Changes in myocardial cells of fetal rats were observed with hematoxylin and eosin ( H&E) staining (A, B 400×; bar, 50 µm) and electron microscopy (C, D 10000×; bar, 1 µm). Hearts were obtained from fetal rats of 21 days gestational age exposed to either saline or AT1-AA before birth from day 13 and 14 of gestational age. A: The myocardial cells control were arranged and tightly stained uniform nuclei with round and clear nucleoli; B: the myocardial nuclei of AT1-AA group was significantly reduced; cells were deranged and swollen. C: myocardial cells arranged in neat rows with integrated mitochondria. D: mitochondrial volume was significantly more increased, and vacuoles enlarge.
  • Figure 4. Effect of prenatal AT1-AA exposure on postischemic recovery of LV function (A-E) and myocardial infarction (F) in 45-day-old rats. Hearts obtained from 45-day-old rats exposed to either saline or AT1-AA (titer 1:640 0.1ml/kg) before birth at day 13 and 14 of gestational age were subjected to 20-min ischemia and 60-min reperfusion in the Langendorff preparation. LVDP, left ventricular developed pressure; HR: heart rate; ±dp/dtmax; the maximal rates of pressure rise/fall; LVEDP: left ventricular end diastolic pressure. LV were collected at the end of reperfusion, and myocardial infarct size was determined with 1% TTC staining and expressed as a percentage of the total LV weight. Data were analyzed by two-way ANOVA with ischemia–reperfusion as one factor and AT1-AA treatment as the other. *P<0.05 compared with control for the entire curve. n=6-8 per group.

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APA

Jin, Z., Zhang, W., Yang, H., Wang, X., Zheng, Y., Zhang, Q., & Zhi, J. (2013). Maternal treatment with agonistic autoantibodies against type-1 angiotensin II receptor in late pregnancy increases apoptosis of myocardial cells and myocardial susceptibility to ischemia-reperfusion injury in offspring rats. PLoS ONE, 8(11). https://doi.org/10.1371/journal.pone.0080709

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