Antenatal Glucocorticoid Administration Promotes Cardiac Structure and Energy Metabolism Maturation in Preterm Fetuses.

Although the rate of preterm birth has increased in recent decades, a number of preterm infants have escaped death due to improvements in perinatal and neonatal care. Antenatal glucocorticoid (GC) therapy has significantly contributed to progression in lung maturation; however, its potential effects on other organs remain controversial. Furthermore, the effects of antenatal GC therapy on the fetal heart show both pros and cons. Translational research in animal models indicates that constant fetal exposure to antenatal GC administration is sufficient for lung maturation. We have established a premature fetal rat model to investigate immature cardiopulmonary functions in the lungs and heart, including the effects of antenatal GC administration. In this review, we explain the mechanisms of antenatal GC actions on the heart in the fetus compared to those in the neonate. Antenatal GCs may contribute to premature heart maturation by accelerating cardiomyocyte proliferation, angiogenesis, energy production, and sarcoplasmic reticulum function. Additionally, this review specifically focuses on fetal heart growth with antenatal GC administration in experimental animal models. Moreover, knowledge regarding antenatal GC administration in experimental animal models can be coupled with that from developmental biology, with the potential for the generation of functional cells and tissues that could be used for regenerative medical purposes in the future.

Exposure of immature rat heart to antenatal glucocorticoid results in cardiac proliferation.

BACKGROUND: ATP synthesis and cardiac contraction-related protein production are accelerated in the immature fetal heart by antenatal glucocorticoids (GC). This study investigated the structural maturity of the myocardium and underlying signal pathway associated with cardiac growth in fetal rats that received antenatal GC. METHODS AND RESULTS: Dexamethasone (DEX) was given to pregnant rats for 2 days from day 17 or day 19 of gestation, and the hearts of 19 and 21 day fetuses and 1-day-old neonates were analyzed. Although irregular myofibril orientation was observed morphologically in 19 day fetal hearts, the myofibril components were organized in fetuses after DEX. The cross-sectional area of the myocardium and Ki-67-positive cells were significantly increased in fetal DEX groups, suggesting that cardiac enlargement resulted from myocyte proliferation. Glycogen synthase kinase-3ß (GSK-3ß) protein was significantly decreased in fetal DEX groups. ß-Catenin and vascular endothelial growth factor protein were also significantly increased. Furthermore, increased cardiomyocyte proliferation appeared to be mediated by GC receptors after culture with DEX in vitro. CONCLUSIONS: Antenatal DEX induces structural maturity accompanying cardiomyocyte proliferation in the premature fetal rat heart, and GSK-3ß and ß-catenin are thought to contribute to cardiac growth.

Infective endocarditis associated with acute leukemia: Report of two cases.

There have been few reports regarding infective endocarditis (IE) in patients with leukemia. In the first case, a 15-year-old girl with Down syndrome was diagnosed with acute lymphoblastic leukemia. On admission, methicillin-sensitive Staphylococcus aureus (MSSA) was detected on blood culture. Echocardiography was performed because MSSA was detected repeatedly even after treatment. Vegetation in all of the atria and ventricles met the Duke criteria defining IE. She died of multiple organ failure 21 days after diagnosis. In the second case, an 11-year-old boy with acute myeloid leukemia underwent peripheral blood stem cell transplantation (PBSCT). He had fever 68 days after PBSCT, and methicillin-resistant S. aureus (MRSA) was detected on blood culture. Echocardiography showed vegetation in the right atrium and ventricle. Daptomycin was administered for 7 weeks, and recurrence was not observed. IE should be considered when S. aureus bacteremia is documented even in patients with leukemia.

Antenatal glucocorticoid therapy accelerates ATP production with creatine kinase increase in the growth-enhanced fetal rat heart.

BACKGROUND: Previous study has demonstrated the increase of several cardiac function-related proteins, including creatine kinase (CK) as an important enzyme in the process of ATP synthesis in the fetal heart of rats administered glucocorticoid (GC) antenatally. In the present study the effect of antenatal GC administration on the CK expression in fetal and neonatal hearts was demonstrated. METHODS AND RESULTS: Dexamethasone was administered to pregnant rats on days 19 and 20 of gestation. The mRNA levels of the CK isoforms, CK-M and Mi-CK, in 21-day-old fetal and 1-day-old neonatal hearts were significantly increased after antenatal GC administration. CK protein levels were also increased in both cultured cardiomyocytes and the mitochondria of the hearts. Uptake of 5, 5', 6, 6'-tetrachloro-1, 1', 3, 3'-tetraethyl-benzimidazolocarbocyanine iodide by mitochondria was significantly increased. An increased ATP level accompanied the CK increase in the neonatal hearts. Furthermore, in vitro these effects were mediated though the GC receptor of cardiomyocytes. Peroxisome proliferator-activated receptor gamma as the upstream transcription factor of CK was significantly increased in fetal hearts. CONCLUSIONS: These results suggest that antenatal GC administration accelerates ATP synthesis through increased CK and may contribute to maturation of the premature heart so that it is ready for preterm delivery. (Circ J 2010; 74: 171 - 180).

A successful treatment of tadalafil in incontinentia pigmenti with pulmonary hypertension.

We describe a female infant with incontinentia pigmenti complicated by severe pulmonary arterial hypertension that was markedly improved by tadalafil administration. The infant was referred to our institution because of neonatal seizures and generalized skin rash at the age of 1 day. She was diagnosed with incontinentia pigmenti on skin biopsy findings. In addition to incontinentia pigmenti, she had pulmonary arterial hypertension without structural heart disease. The pulmonary hypertension rapidly worsened at the age of 2 months and was confirmed by cardiac catheterization. The pulmonary artery pressure was equal to systemic pressure but it decreased in response to nitric oxide inhalation. We, therefore, initiated treatment with tadalafil of 1 mg/kg/day. The follow-up cardiac catheterization performed at 9 months revealed dramatic improvement in the pulmonary artery pressure. An IKBKG mutation with deletion of exons 4-10 was detected in the blood of both the patient and her mother. Our experience indicates that tadalafil may be beneficial in treating pulmonary arterial hypertension associated with incontinentia pigmenti.

Fasudil attenuates sympathetic nervous activity in the adrenal medulla of spontaneously hypertensive rats.

We investigated the effects of fasudil, a Rho kinase inhibitor, on hypertension in spontaneously hypertensive rats and on the catecholamine synthetic pathway. Ten-week-old male SHR and Wistar-Kyoto rats were administered fasudil (10 mg/kg/day s.c.) for 4 days. Systolic blood pressure was measured using the tail-cuff method. Catecholamine levels were measured with high-performance liquid chromatography-ECD methods. Tyrosine hydroxylase protein levels were measured in Western blot analysis. The tyrosine hydroxylase mRNA level was measured using real-time PCR methods. Fasudil significantly decreased systolic blood pressure in spontaneously hypertensive rats, but not in Wistar-Kyoto rats. Fasudil also significantly decreased catecholamine, tyrosine hydroxylase protein, and tyrosine hydroxylase mRNA levels in the adrenal medulla of spontaneously hypertensive rats. These results suggest that the depressor effects of fasudil on hypertension in spontaneously hypertensive rats may be related to inhibition of the catecholamine synthetic pathway.

Arrhythmia risk and ß-blocker therapy in pregnant women with long QT syndrome.

BACKGROUND: Pregnancy is one of the biggest concerns for women with long QT syndrome (LQTS). OBJECTIVES: This study investigated pregnancy-related arrhythmic risk and the efficacy and safety of ß-blocker therapy for lethal ventricular arrhythmias in pregnant women with LQTS (LQT-P) and their babies. METHODS: 136 pregnancies in 76 LQT-P (29±5 years old; 22 LQT1, 36 LQT2, one LQT3, and 17 genotype-unknown) were enrolled. We retrospectively analysed their clinical and electrophysiological characteristics and pregnancy outcomes in the presence (BB group: n=42) or absence of ß-blocker therapy (non-BB group: n=94). RESULTS: All of the BB group had been diagnosed with LQTS with previous events, whereas 65% of the non-BB group had not been diagnosed at pregnancy. Pregnancy increased heart rate in the non-BB group; however, no significant difference was observed in QT and Tpeak-Tend intervals between the two groups. In the BB group, only two events occurred at postpartum, whereas 12 events occurred in the non-BB group during pregnancy (n=6) or postpartum period (n=6). The frequency of spontaneous abortion did not differ between the two groups. Fetal growth rate and proportion of infants with congenital malformation were similar between the two groups, but premature delivery and low birthweight infants were more common in those taking BB (OR 4.79, 95% CI 1.51 to 15.21 and OR 3.25, 95% CI 1.17 to 9.09, respectively). CONCLUSIONS: Early diagnosis and ß-blocker therapy for high-risk patients with LQTS are important for prevention of cardiac events during pregnancy and the postpartum period, and ß-blocker therapy may be tolerated for babies in LQT-P cases.

Antenatal glucocorticoid therapy increase cardiac alpha-enolase levels in fetus and neonate rats.

AIMS: Antenatal glucocorticoid therapy has been shown to prevent acute diseases including infant respiratory distress syndrome and reduce mortality, although little is known about the effects on cardiac function-related proteins in the fetus or neonate. We investigated whether cardiac function-related proteins were altered in cardiac tissues of fetuses and neonates born to pregnant rats treated by glucocorticoid. MAIN METHODS: Dexamethasone (DEX) was administered to pregnant rats for 2 days on day 17 and 18 or day 19 and 20 of gestation to simulate antenatal DEX therapy, and cardiac tissues of 19- and 21-day fetuses and 1-, 3-, and 5-day neonates were analyzed using a proteomic technique with liquid chromatography-mass spectrometry/mass spectrometry. KEY FINDINGS: The identified five proteins; alpha-enolase, creatine kinase-M type, beta-tubulin, troponin T, and ATP synthase beta-chain, were significantly increased in fetal cardiac tissues with DEX administration. We observed that significant increase of alpha-enolase in the 19-day fetuses by DEX using Western blotting and immunohistochemistry. ATP and cAMP levels were also increased in the fetal heart tissue. In addition, pyruvate levels were significantly increased in the fetus groups by DEX. SIGNIFICANCE: These results suggest that increased alpha-enolase may contribute to acceleration of glycolysis in the preterm heart.

Effects of antenatal dexamethasone on antioxidant enzymes and nitric oxide synthase in the rat lung.

We investigated the effects of prenatal dexamethasone (DEX) administration on antioxidant enzymes (AOEs) and nitric oxide synthase (NOS) in fetal and neonatal rat lungs. DEX (1 mg/kg, s.c., for 2 days) or vehicle alone was administered to pregnant rats, and the lungs of fetuses on days 19 and 21 of gestation and of 1- and 3-day-old neonates were examined. We measured protein levels of the AOEs manganese superoxide dismutase and copper-zinc superoxide dismutase (Mn SOD and Cu-Zn SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and inducible and endothelial nitric oxide synthase (i-NOS and e-NOS). Mn SOD, GSH-Px, and e-NOS expression gradually increased with increasing gestational and postnatal age in the lungs of the control groups. Cu-Zn SOD, CAT, and i-NOS expression did not change with increasing gestational and postnatal age in the lungs of the control groups. DEX administration had significant effects on i-NOS and e-NOS protein and mRNA expression. The increased Mn SOD, GSH-Px, and e-NOS expressions during the perinatal period suggests that antenatal developmental changes in AOEs in the lungs of premature fetuses could be reduced by reactive oxygen species-mediated injury at birth. Furthermore, antenatal glucocorticoid treatment may accelerate the development of lungs via the two types of NOS.

Irinotecan activates p53 with its active metabolite, resulting in human hepatocellular carcinoma apoptosis.

The topoisomerase I inhibitor irinotecan is widely used in anticancer therapy, although the detailed mechanism is still unclear. We investigated the apoptotic mechanisms of irinotecan in human hepatocellular carcinoma (HCC) cell lines (Huh7). SN-38 caused a significant decrease in cell proliferation and induced apoptosis in Huh7 cells and HepG2 cells. SN-38 significantly increased the expression of p53 protein and its phosphorylation at Ser(15) in the nucleus and apoptosis-inducing proteins Bax, caspase-9, and caspase-3, while it significantly decreased the antiapoptosis protein Bcl-xL of Huh7 cells. SN-38-induced apoptosis was recovered after p53 antisense oligodeoxynucleotide (AS ODN) pretreatment, while Huh7 cells were precultured with p53 AS ODN, followed by the addition of SN-38 for 24 h. Furthermore, increases in p53 DNA-binding activity were observed in the nuclei of Huh7 cells after SN-38 treatment as shown by electrophoretic mobility shift analysis. SN-38 binding motifs were detected in the proximal promoter of p53 (bases -433 to -317 and -814 to -711). These results suggest that the p53-mediated apoptosis pathway is important in the anticancer effects of irinotecan in hepatocellular carcinoma.

The elucidation of the mechanism of weight gain and glucose tolerance abnormalities induced by chlorpromazine.

Antipsychotic drugs induce weight gain and metabolic abnormalities. Recently, the role of adipocytokines secreted from adipocytes in the development of metabolic syndrome has received attention. The aim of this study was to investigate the effects of chlorpromazine (Cp) on body weight, glucose, lipid metabolism, and adipocytokine secretion in rats fed sucrose. Wistar rats received 15% sucrose (Suc group), 15% sucrose and Cp at 7.5 mg/kg per day (Suc + Cp group), or Cp alone (Cp group) in water for 10 weeks. Fasting glucose levels in the Suc and Suc + Cp groups were significantly higher than in the control (Cont) group. Fasting insulin levels in the Suc, Suc + Cp, and Cp groups were also significantly higher than in the Cont group. The adiponectin level in the Suc group was significantly higher than in the Cont group, although the adiponectin level in the Suc + Cp group was not. Furthermore, the plasma tumor necrosis factor (TNF)-alpha level in the Suc + Cp group was significantly higher than in the Suc group. These data suggest that Cp inhibits the compensatory response of adiponectin with respect to obesity due to increased expression of plasma TNF-alpha level. Cp may exert more harmful effects on the glucose level and insulin resistance than on other factors, which may be one of the mechanisms responsible for the metabolic syndrome induced by antipsychotic agents.