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Protective Effects of Valproic Acid, a Histone Deacetylase Inhibitor, against Hyperoxic Lung Injury in a Neonatal Rat Model.

Cetinkaya M, Cansev M, Cekmez F, Tayman C, Canpolat FE, Kafa IM, Yaylagul EO, Kramer BW, Sarici SU - PLoS ONE (2015)

Bottom Line: Expressions of TGFβ3 and phospho-SMAD2 proteins and levels of tissue proinflammatory cytokines as well as lipid peroxidation biomarkers were reduced, while anti-oxidative enzyme activities were enhanced by VPA treatment.VPA administration also reduced HDAC activity while increasing acetylated H3 and H4 protein expressions.The preventive effect of VPA involves HDAC inhibition.

View Article: PubMed Central - PubMed

Affiliation: Gulhane Military Medical Academy, Department of Pediatrics, Division of Neonatology, Ankara, Turkey.

ABSTRACT

Objective: Histone acetylation and deacetylation may play a role in the pathogenesis of inflammatory lung diseases. We evaluated the preventive effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, on neonatal hyperoxic lung injury.

Methods: Forty newborn rat pups were randomized in normoxia, normoxia+VPA, hyperoxia and hyperoxia+VPA groups. Pups in the normoxia and normoxia+VPA groups were kept in room air and received daily saline and VPA (30 mg/kg) injections, respectively, while those in hyperoxia and hyperoxia+VPA groups were exposed to 95% O2 and received daily saline and VPA (30 mg/kg) injections for 10 days, respectively. Growth, histopathological, biochemical and molecular biological indicators of lung injury, apoptosis, inflammation, fibrosis and histone acetylation were evaluated.

Results: VPA treatment during hyperoxia significantly improved weight gain, histopathologic grade, radial alveolar count and lamellar body membrane protein expression, while it decreased number of TUNEL(+) cells and active Caspase-3 expression. Expressions of TGFβ3 and phospho-SMAD2 proteins and levels of tissue proinflammatory cytokines as well as lipid peroxidation biomarkers were reduced, while anti-oxidative enzyme activities were enhanced by VPA treatment. VPA administration also reduced HDAC activity while increasing acetylated H3 and H4 protein expressions.

Conclusions: The present study shows for the first time that VPA treatment ameliorates lung damage in a neonatal rat model of hyperoxic lung injury. The preventive effect of VPA involves HDAC inhibition.

No MeSH data available.


Related in: MedlinePlus

Bar graphs depicting histone deacetylase (HDAC) activity (A) as well as acetylated histone H3 (B) and acetylated histone H4 (C) protein expressions in lung tissues of rat pups.*p<0.05 and **p<0.001 compared to Normoxia group; #p<0.05 and ##p<0.001 compared to Normoxia+VPA group; and ††p<0.001 compared to Hyperoxia group using One-Way ANOVA followed by post-hoc Tukey test.
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pone.0126028.g007: Bar graphs depicting histone deacetylase (HDAC) activity (A) as well as acetylated histone H3 (B) and acetylated histone H4 (C) protein expressions in lung tissues of rat pups.*p<0.05 and **p<0.001 compared to Normoxia group; #p<0.05 and ##p<0.001 compared to Normoxia+VPA group; and ††p<0.001 compared to Hyperoxia group using One-Way ANOVA followed by post-hoc Tukey test.

Mentions: HDAC activity was analyzed in order to test our hypothesis that VPA administration affected epigenetic regulation of pulmonary inflammation in this hyperoxic lung injury model. HDAC activity in lung tissues was found to be significantly enhanced (p<0.05) in Hyperoxia group compared to Normoxia and Normoxia+VPA groups. VPA treatment reduced the increased HDAC activity significantly (p<0.05) (Fig 7A). Consistently, acetyl-histone H3 and H4 protein expressions in Hyperoxia+VPA group were significantly (p<0.001) increased compared with Hyperoxia group (Fig 7B & 7C, respectively).


Protective Effects of Valproic Acid, a Histone Deacetylase Inhibitor, against Hyperoxic Lung Injury in a Neonatal Rat Model.

Cetinkaya M, Cansev M, Cekmez F, Tayman C, Canpolat FE, Kafa IM, Yaylagul EO, Kramer BW, Sarici SU - PLoS ONE (2015)

Bar graphs depicting histone deacetylase (HDAC) activity (A) as well as acetylated histone H3 (B) and acetylated histone H4 (C) protein expressions in lung tissues of rat pups.*p<0.05 and **p<0.001 compared to Normoxia group; #p<0.05 and ##p<0.001 compared to Normoxia+VPA group; and ††p<0.001 compared to Hyperoxia group using One-Way ANOVA followed by post-hoc Tukey test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4418724&req=5

pone.0126028.g007: Bar graphs depicting histone deacetylase (HDAC) activity (A) as well as acetylated histone H3 (B) and acetylated histone H4 (C) protein expressions in lung tissues of rat pups.*p<0.05 and **p<0.001 compared to Normoxia group; #p<0.05 and ##p<0.001 compared to Normoxia+VPA group; and ††p<0.001 compared to Hyperoxia group using One-Way ANOVA followed by post-hoc Tukey test.
Mentions: HDAC activity was analyzed in order to test our hypothesis that VPA administration affected epigenetic regulation of pulmonary inflammation in this hyperoxic lung injury model. HDAC activity in lung tissues was found to be significantly enhanced (p<0.05) in Hyperoxia group compared to Normoxia and Normoxia+VPA groups. VPA treatment reduced the increased HDAC activity significantly (p<0.05) (Fig 7A). Consistently, acetyl-histone H3 and H4 protein expressions in Hyperoxia+VPA group were significantly (p<0.001) increased compared with Hyperoxia group (Fig 7B & 7C, respectively).

Bottom Line: Expressions of TGFβ3 and phospho-SMAD2 proteins and levels of tissue proinflammatory cytokines as well as lipid peroxidation biomarkers were reduced, while anti-oxidative enzyme activities were enhanced by VPA treatment.VPA administration also reduced HDAC activity while increasing acetylated H3 and H4 protein expressions.The preventive effect of VPA involves HDAC inhibition.

View Article: PubMed Central - PubMed

Affiliation: Gulhane Military Medical Academy, Department of Pediatrics, Division of Neonatology, Ankara, Turkey.

ABSTRACT

Objective: Histone acetylation and deacetylation may play a role in the pathogenesis of inflammatory lung diseases. We evaluated the preventive effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, on neonatal hyperoxic lung injury.

Methods: Forty newborn rat pups were randomized in normoxia, normoxia+VPA, hyperoxia and hyperoxia+VPA groups. Pups in the normoxia and normoxia+VPA groups were kept in room air and received daily saline and VPA (30 mg/kg) injections, respectively, while those in hyperoxia and hyperoxia+VPA groups were exposed to 95% O2 and received daily saline and VPA (30 mg/kg) injections for 10 days, respectively. Growth, histopathological, biochemical and molecular biological indicators of lung injury, apoptosis, inflammation, fibrosis and histone acetylation were evaluated.

Results: VPA treatment during hyperoxia significantly improved weight gain, histopathologic grade, radial alveolar count and lamellar body membrane protein expression, while it decreased number of TUNEL(+) cells and active Caspase-3 expression. Expressions of TGFβ3 and phospho-SMAD2 proteins and levels of tissue proinflammatory cytokines as well as lipid peroxidation biomarkers were reduced, while anti-oxidative enzyme activities were enhanced by VPA treatment. VPA administration also reduced HDAC activity while increasing acetylated H3 and H4 protein expressions.

Conclusions: The present study shows for the first time that VPA treatment ameliorates lung damage in a neonatal rat model of hyperoxic lung injury. The preventive effect of VPA involves HDAC inhibition.

No MeSH data available.


Related in: MedlinePlus