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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

The effects of different HDAC inhibitors on H3 Acetylation.(A,B) Western blots of H3 acetylation in cultured neonatal cardiomyocytes treated with different concentrations of PBA for 24 h (A) or with 5 mM PBA for different periods (0, 6, 12, 24 and 48 h) (B). n = 4 in each group. (C–E) Western blots of H3 acetylation in cultured neonatal cardiomyocytes treated with different concentrations of BS (C), VAL (D) or TSA (E) for 24 h. n = 4 in each group. Data are expressed as mean ± SEM; *P < 0.05 vs. baseline. The blots in (A–E) were cropped from Fig. S1E–I, respectively. All the gels were run under the same experimental conditions.
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f8: The effects of different HDAC inhibitors on H3 Acetylation.(A,B) Western blots of H3 acetylation in cultured neonatal cardiomyocytes treated with different concentrations of PBA for 24 h (A) or with 5 mM PBA for different periods (0, 6, 12, 24 and 48 h) (B). n = 4 in each group. (C–E) Western blots of H3 acetylation in cultured neonatal cardiomyocytes treated with different concentrations of BS (C), VAL (D) or TSA (E) for 24 h. n = 4 in each group. Data are expressed as mean ± SEM; *P < 0.05 vs. baseline. The blots in (A–E) were cropped from Fig. S1E–I, respectively. All the gels were run under the same experimental conditions.

Mentions: The acetylated H3 levels in the cultured cardiomyocytes were analysed by western blotting. As shown in Fig. 8A,B, PBA treatment inhibited HDAC activity in a time- and dose-dependent manner. Exposure to PBA, even at a low dose of 0.1 mmol/L, induced hyperacetylation of H3. Similarly, BS, VAL and TSA promoted H3 acetylation in a dose-dependent manner (Fig. 8C–E).


Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition
The effects of different HDAC inhibitors on H3 Acetylation.(A,B) Western blots of H3 acetylation in cultured neonatal cardiomyocytes treated with different concentrations of PBA for 24 h (A) or with 5 mM PBA for different periods (0, 6, 12, 24 and 48 h) (B). n = 4 in each group. (C–E) Western blots of H3 acetylation in cultured neonatal cardiomyocytes treated with different concentrations of BS (C), VAL (D) or TSA (E) for 24 h. n = 4 in each group. Data are expressed as mean ± SEM; *P < 0.05 vs. baseline. The blots in (A–E) were cropped from Fig. S1E–I, respectively. All the gels were run under the same experimental conditions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036044&req=5

f8: The effects of different HDAC inhibitors on H3 Acetylation.(A,B) Western blots of H3 acetylation in cultured neonatal cardiomyocytes treated with different concentrations of PBA for 24 h (A) or with 5 mM PBA for different periods (0, 6, 12, 24 and 48 h) (B). n = 4 in each group. (C–E) Western blots of H3 acetylation in cultured neonatal cardiomyocytes treated with different concentrations of BS (C), VAL (D) or TSA (E) for 24 h. n = 4 in each group. Data are expressed as mean ± SEM; *P < 0.05 vs. baseline. The blots in (A–E) were cropped from Fig. S1E–I, respectively. All the gels were run under the same experimental conditions.
Mentions: The acetylated H3 levels in the cultured cardiomyocytes were analysed by western blotting. As shown in Fig. 8A,B, PBA treatment inhibited HDAC activity in a time- and dose-dependent manner. Exposure to PBA, even at a low dose of 0.1 mmol/L, induced hyperacetylation of H3. Similarly, BS, VAL and TSA promoted H3 acetylation in a dose-dependent manner (Fig. 8C–E).

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