Long-term cardiovascular effects of neonatal dexamethasone treatment: hemodynamic follow-up by left ventricular pressure-volume loops in rats

Bal, Miriam P; Vries, Willem B. de; Oosterhout, Matthijs F.M. van; Baan, Jan; Wall, Ernst E. van der; Bel, Frank van; Steendijk, Paul

doi:10.1152/japplphysiol.00951.2007

Cited by 32 publications

(29 citation statements)

References 43 publications

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“…In the young Dex-treated rats, Vw was reduced despite this cellular hypertrophy later in life, but in the 50-wk-old animals in which also myocyte width was increased substantially, these hypertrophic processes are likely to be compensatory. Despite these compensatory mechanisms, we recently reported on the loss of systolic cardiac function in this group of 50-wk-old Dex-treated rats (15), which may indicate that cardiomyocyte hypertrophy did not fully compensate for the lower number of cardiomyocytes. Furthermore, histologic analysis of the 50-wk-old Dex-treated hearts revealed more foci of inflammation associated with myocytolysis, which may indicate "wear-out" of the remaining cardiomyocytes.…”

Section: Discussionmentioning

confidence: 67%

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Histopathological Changes of the Heart After Neonatal Dexamethasone Treatment: Studies in 4-, 8-, and 50-Week-Old Rats

et al. 2009

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Dexamethasone (Dex), for prevention of chronic lung disease in preterm infants, showed potential negative long-term effects. Studies regarding long-term cardiovascular effects are lacking. We investigated possible histopathological myocardial changes after neonatal Dex in the young and adult rat heart. Rats were treated with Dex on d 1, 2, and 3 (0.5, 0.3, and 0.1 mg/kg) of life. Control-pups received saline. At 4, 8, and 50 wk after birth rats were killed and anatomic data collected. Heart tissue was stained with hematoxylin and eosin, Cadherin-periodic acid schiff, and sirius red for cardiomyocyte morphometry and collagen determination. Presence of macrophages and mast cells was analyzed. Cardiomyocyte length of the Dex-treated rats was increased in all three age groups, whereas ventricular weight was reduced. Cardiomyocyte volumes were increased at 50 wk indicating cellular hypertrophy. Collagen content gradually increased with age and was 62% higher in Dex rats at 50 wk. Macrophage focus score and mast cell count were also higher. Neonatal Dex affects normal heart growth resulting in cellular hypertrophy and increased collagen deposition in the adult rat heart. Because previous studies in rats showed premature death, suggesting cardiac failure, cardiovascular follow-up of preterm infants treated with glucocorticoids should be considered. (Pediatr Res 66: 74-79, 2009)

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Section: Discussionmentioning

confidence: 67%

“…The rats were weaned on d 21 and studied at 4, 8, or 50 wk of age. Before being killed for the current histopathological study, hemodynamic measurements were performed that were reported elsewhere (14,15). All groups at the various ages (4-, 8-, and 50-wk-old) consisted of eight rats.…”

Section: Animals the Study Protocol Was Approved By The Animal Researchmentioning

confidence: 99%

Histopathological Changes of the Heart After Neonatal Dexamethasone Treatment: Studies in 4-, 8-, and 50-Week-Old Rats

et al. 2009

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“…Yet synthetic glucocorticoid exposure may be harmful to other tissues and organs (Ortiz et al, 2003;Shoener et al, 2006;Kamphuis et al, 2007;Bal et al, 2008;Davis et al, 2011;Kelly et al, 2012). Recently, we demonstrated that treatment of newborn rats with dexamethasone during a critical window of the heart development inhibited cardiomyocyte proliferation, stimulated premature cardiomyocyte binucleation, and reduced the total cardiomyocyte number in the heart .…”

Section: Introductionmentioning

confidence: 98%

Dexamethasone Induces Cardiomyocyte Terminal Differentiation via Epigenetic Repression of Cyclin D2 Gene

Dasgupta

Kanna

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Dexamethasone treatment of newborn rats inhibited cardiomyocyte proliferation and stimulated premature terminal differentiation of cardiomyocytes in the developing heart. Yet mechanisms remain undetermined. The present study tested the hypothesis that the direct effect of glucocorticoid receptor-mediated epigenetic repression of cyclin D2 gene in the cardiomyocyte plays a key role in the dexamethasone-mediated effects in the developing heart. Cardiomyocytes were isolated from 2-day-old rats. Cells were stained with a cardiomyocyte marker a-actinin and a proliferation marker Ki67. Cyclin D2 expression was evaluated by Western blot and quantitative real-time polymerase chain reaction. Promoter methylation of CcnD2 was determined by methylated DNA immunoprecipitation (MeDIP). Overexpression of Cyclin D2 was conducted by transfection of FlexiCcnD2 (1CcnD2) construct. Treatment of cardiomyocytes isolated from newborn rats with dexamethasone for 48 hours significantly inhibited cardiomyocyte proliferation with increased binucleation and decreased cyclin D2 protein abundance. These effects were blocked with Ru486 (mifepristone). In addition, the dexamethasone treatment significantly increased cyclin D2 gene promoter methylation in newborn rat cardiomyocytes. 5-Aza-2'-deoxycytidine inhibited dexamethasone-mediated promoter methylation, recovered dexamethasone-induced cyclin D2 gene repression, and blocked the dexamethasone-elicited effects on cardiomyocyte proliferation and binucleation. In addition, the overexpression of cyclin D2 restored the dexamethasone-mediated inhibition of proliferation and increase in binucleation in newborn rat cardiomyocytes. The results demonstrate that dexamethasone acting on glucocorticoid receptors has a direct effect and inhibits proliferation and stimulates premature terminal differentiation of cardiomyocytes in the developing heart via epigenetic repression of cyclin D2 gene.

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“…Excessive 'catch-up' growth may be compounded when hypertension development associated with exposure to elevated systemic glucocorticoid levels contributes to cardiac loading. Recent studies by Bal et al [45,46] suggest that neonatal dexamethasone treatment is associated with cellular hypertrophy, increased collagen deposition and systolic dysfunction in the adult rat heart at 50 weeks of age. Interestingly, following neonatal dexamethasone exposure, the ventricular weight to body weight ratio was reduced at 4 weeks of age, but was not different at 50 weeks of age, indicative of partial cardiac 'catch-up' growth.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids Suppress Growth in Neonatal Cardiomyocytes Co-Expressing AT<sub>2</sub> and AT<sub>1</sub> Angiotensin Receptors

et al. 2009

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Background: Perinatal glucocorticoid treatment is associated with hypertrophic cardiomyopathy, but the cellular mechanism is controversial. An underlying interaction between glucocorticoids and the renin-angiotensin system may be important, but whether glucocorticoids modulate angiotensin II (AngII)-dependent cardiomyocyte growth responses in the neonate has not been investigated. Objectives: The major aim of this investigation was to determine whether glucocorticoids modulate the neonatal cardiomyocyte growth response to AngII. In particular we sought evidence to determine whether angiotensin II type 2 (AT₂) receptor co-expression with angiotensin II type 1 (AT₁) receptor is of specific importance in this modulatory function. Methods: In this study, we used AT₁ and AT₂ receptor-expressing adenoviruses (Ad-AT₁ and Ad-AT₂) in a well-defined in vitro neonatal cardiomyocyte culture model to assess whether glucocorticoids affect cardiomyocyte growth responses (i.e. total protein content). Results: Following addition of AngII (0.1 µmol/l) to neonatal cardiomyocytes infected with Ad-AT₁ alone, a significant growth response was measured (133.2 ± 4.8%). Expression of Ad-AT₂ alone induced a ∼20% increase in total cellular protein content, which was unaffected by addition of AngII. Neither corticosterone (1 µmol/l) nor dexamethasone (1 µmol/l) had any significant effect on the AT₁- or AT₂-mediated growth responses. In contrast, the growth response to AngII was augmented following co-expression of AT₂ and AT₁ receptors (149.2 ± 4.2%), which was reduced by ∼20% in the presence of either corticosterone or dexamethasone (p < 0.05). Conclusions: The present study provides novel evidence that glucocorticoids suppress neonatal cardiomyocyte growth responsiveness when AT₂and AT₁ receptor subtypes are co-expressed.

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Long-term cardiovascular effects of neonatal dexamethasone treatment: hemodynamic follow-up by left ventricular pressure-volume loops in rats

Cited by 32 publications

References 43 publications

Histopathological Changes of the Heart After Neonatal Dexamethasone Treatment: Studies in 4-, 8-, and 50-Week-Old Rats

Histopathological Changes of the Heart After Neonatal Dexamethasone Treatment: Studies in 4-, 8-, and 50-Week-Old Rats

Dexamethasone Induces Cardiomyocyte Terminal Differentiation via Epigenetic Repression of Cyclin D2 Gene

Glucocorticoids Suppress Growth in Neonatal Cardiomyocytes Co-Expressing AT<sub>2</sub> and AT<sub>1</sub> Angiotensin Receptors

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