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Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition

View Article: PubMed Central - PubMed

ABSTRACT

4-Sodium phenylbutyrate (PBA) has been reported to inhibit endoplasmic reticulum stress and histone deacetylation (HDAC), both of which are novel therapeutic targets for cardiac hypertrophy and heart failure. However, it is unclear whether PBA can improve heart function. Here, we tested the effects of PBA and some other HDAC inhibitors on cardiac dysfunction induced by pressure overload. Transverse aortic constriction (TAC) was performed on male C57BL/6 mice. PBA treatment (100 mg/kg, 6 weeks) unexpectedly led to a higher mortality, exacerbated cardiac remodelling and dysfunction. Similar results were noted in TAC mice treated with butyrate sodium (BS), a PBA analogue. In contrast, other HDAC inhibitors, valproic acid (VAL) and trichostatin A (TSA), improved the survival. All four HDAC inhibitors induced histone H3 acetylation and inhibited HDAC total activity. An individual HDAC activity assay showed that rather than class IIa members (HDAC4 and 7), PBA and BS predominantly inhibited class I members (HDAC2 and 8), whereas VAL and TSA inhibited all of them. These findings indicate that PBA and BS accelerate cardiac hypertrophy and dysfunction, whereas VAL and TSA have opposing effects.

No MeSH data available.


Related in: MedlinePlus

Effects of PBA on the expression of ANP, BNP, histone H3 acetylation, CHOP and JNK activity 6 weeks after surgery.(A) Representative western blots of myocardial ANP (atrial natriuretic peptide; cropped from Fig. S1A). n = 4 in each group. (B) mRNA level of BNP (brain natriuretic peptide) determined by real-time PCR. n = 4 in each group. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. (C–E) Western blots of myocardial histone H3 (H3) acetylation (C) C/EBP homologous protein (CHOP) (D) and JNK phosphorylation (E). These blots were cropped from Fig. S1B–D, respectively. n = 4 in each group. *P < 0.05. Data are expressed as mean ± SEM. TAC, transverse aortic constriction. All the gels have been run under the same experimental conditions.
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f6: Effects of PBA on the expression of ANP, BNP, histone H3 acetylation, CHOP and JNK activity 6 weeks after surgery.(A) Representative western blots of myocardial ANP (atrial natriuretic peptide; cropped from Fig. S1A). n = 4 in each group. (B) mRNA level of BNP (brain natriuretic peptide) determined by real-time PCR. n = 4 in each group. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. (C–E) Western blots of myocardial histone H3 (H3) acetylation (C) C/EBP homologous protein (CHOP) (D) and JNK phosphorylation (E). These blots were cropped from Fig. S1B–D, respectively. n = 4 in each group. *P < 0.05. Data are expressed as mean ± SEM. TAC, transverse aortic constriction. All the gels have been run under the same experimental conditions.

Mentions: TAC surgery remarkably increased the cardiac expression levels of the hypertrophic markers, atrial natriuretic factor (ANP) and brain natriuretic peptide (BNP), while PBA (100 mg/kg/d) remarkably augmented these upregulation effects (Fig. 6A,B). The acetylated histone H3 levels were significantly elevated in PBA-treated TAC or sham mice (Fig. 6C), indicating that PBA successfully inhibited the total HDAC activity. TAC mice also displayed an increased cardiac acetylated histone H3 (H3) level compared with the sham mice (Fig. 6C). C/EBP homologous protein (CHOP), an ER stress-related protein, was significantly induced in the TAC group and was moderately but significantly inhibited by PBA treatment (Fig. 6D). The phosphorylation of c-Jun N-terminal kinase (JNK), a recently reported anti-hypertrophic factor19, was markedly increased in TAC mice and was robustly downregulated by PBA treatment (Fig. 6E).


Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition
Effects of PBA on the expression of ANP, BNP, histone H3 acetylation, CHOP and JNK activity 6 weeks after surgery.(A) Representative western blots of myocardial ANP (atrial natriuretic peptide; cropped from Fig. S1A). n = 4 in each group. (B) mRNA level of BNP (brain natriuretic peptide) determined by real-time PCR. n = 4 in each group. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. (C–E) Western blots of myocardial histone H3 (H3) acetylation (C) C/EBP homologous protein (CHOP) (D) and JNK phosphorylation (E). These blots were cropped from Fig. S1B–D, respectively. n = 4 in each group. *P < 0.05. Data are expressed as mean ± SEM. TAC, transverse aortic constriction. All the gels have been run under the same experimental conditions.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036044&req=5

f6: Effects of PBA on the expression of ANP, BNP, histone H3 acetylation, CHOP and JNK activity 6 weeks after surgery.(A) Representative western blots of myocardial ANP (atrial natriuretic peptide; cropped from Fig. S1A). n = 4 in each group. (B) mRNA level of BNP (brain natriuretic peptide) determined by real-time PCR. n = 4 in each group. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. (C–E) Western blots of myocardial histone H3 (H3) acetylation (C) C/EBP homologous protein (CHOP) (D) and JNK phosphorylation (E). These blots were cropped from Fig. S1B–D, respectively. n = 4 in each group. *P < 0.05. Data are expressed as mean ± SEM. TAC, transverse aortic constriction. All the gels have been run under the same experimental conditions.
Mentions: TAC surgery remarkably increased the cardiac expression levels of the hypertrophic markers, atrial natriuretic factor (ANP) and brain natriuretic peptide (BNP), while PBA (100 mg/kg/d) remarkably augmented these upregulation effects (Fig. 6A,B). The acetylated histone H3 levels were significantly elevated in PBA-treated TAC or sham mice (Fig. 6C), indicating that PBA successfully inhibited the total HDAC activity. TAC mice also displayed an increased cardiac acetylated histone H3 (H3) level compared with the sham mice (Fig. 6C). C/EBP homologous protein (CHOP), an ER stress-related protein, was significantly induced in the TAC group and was moderately but significantly inhibited by PBA treatment (Fig. 6D). The phosphorylation of c-Jun N-terminal kinase (JNK), a recently reported anti-hypertrophic factor19, was markedly increased in TAC mice and was robustly downregulated by PBA treatment (Fig. 6E).

View Article: PubMed Central - PubMed

ABSTRACT

4-Sodium phenylbutyrate (PBA) has been reported to inhibit endoplasmic reticulum stress and histone deacetylation (HDAC), both of which are novel therapeutic targets for cardiac hypertrophy and heart failure. However, it is unclear whether PBA can improve heart function. Here, we tested the effects of PBA and some other HDAC inhibitors on cardiac dysfunction induced by pressure overload. Transverse aortic constriction (TAC) was performed on male C57BL/6 mice. PBA treatment (100&thinsp;mg/kg, 6 weeks) unexpectedly led to a higher mortality, exacerbated cardiac remodelling and dysfunction. Similar results were noted in TAC mice treated with butyrate sodium (BS), a PBA analogue. In contrast, other HDAC inhibitors, valproic acid (VAL) and trichostatin A (TSA), improved the survival. All four HDAC inhibitors induced histone H3 acetylation and inhibited HDAC total activity. An individual HDAC activity assay showed that rather than class IIa members (HDAC4 and 7), PBA and BS predominantly inhibited class I members (HDAC2 and 8), whereas VAL and TSA inhibited all of them. These findings indicate that PBA and BS accelerate cardiac hypertrophy and dysfunction, whereas VAL and TSA have opposing effects.

No MeSH data available.


Related in: MedlinePlus