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

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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.


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Inhibition of different HDAC subtypes by individual inhibitors in neonatal rat cardiomyocytes.(A–D) Active recombinant HDAC2, 4, 7 or 8 was incubated with a specific unique fluorogenic substrate in the presence or absence of the HDAC inhibitor, PBA (A), BS (B), TSA (C) or VAL (D), at different doses. The system’s fluorescence intensity was measured using a fluorescence reader after adding Lysine Developer. Data are expressed as mean ± SEM; n = 3; *P < 0.05 vs. the corresponding baseline of each HDAC subtype.
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f1: Inhibition of different HDAC subtypes by individual inhibitors in neonatal rat cardiomyocytes.(A–D) Active recombinant HDAC2, 4, 7 or 8 was incubated with a specific unique fluorogenic substrate in the presence or absence of the HDAC inhibitor, PBA (A), BS (B), TSA (C) or VAL (D), at different doses. The system’s fluorescence intensity was measured using a fluorescence reader after adding Lysine Developer. Data are expressed as mean ± SEM; n = 3; *P < 0.05 vs. the corresponding baseline of each HDAC subtype.

Mentions: We investigated the inhibitory spectrum of PBA, BS, VAL and TSA with regard to individual HDAC2, 4, 7 and 8. All four inhibitors inhibited HDAC2 and 8 (class I) potently, while they differed a lot in regard to HDAC4 and 7 (class IIa) (Fig. 1). Similar to their effects on class I HDACs, VAL and TSA also robustly inhibited HDAC4 and 7 (Fig. 1C,D). In contrast, PBA and BS had modest or even no obvious inhibitory effect on these class IIa HDACs (Fig. 1A,B), although toxic doses of PBA (>25 mM) significantly inhibited them. Because it has been proposed that activation of class I members is pro-hypertrophic, while activation of class IIa suppresses cardiac hypertrophy1215161718, we postulated that PBA should have a more potent anti-hypertrophic effect than nonselective HDAC inhibitors. Thus, we next determined the role of PBA in pressure overload-induced cardiac remodelling.


Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition
Inhibition of different HDAC subtypes by individual inhibitors in neonatal rat cardiomyocytes.(A–D) Active recombinant HDAC2, 4, 7 or 8 was incubated with a specific unique fluorogenic substrate in the presence or absence of the HDAC inhibitor, PBA (A), BS (B), TSA (C) or VAL (D), at different doses. The system’s fluorescence intensity was measured using a fluorescence reader after adding Lysine Developer. Data are expressed as mean ± SEM; n = 3; *P < 0.05 vs. the corresponding baseline of each HDAC subtype.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Inhibition of different HDAC subtypes by individual inhibitors in neonatal rat cardiomyocytes.(A–D) Active recombinant HDAC2, 4, 7 or 8 was incubated with a specific unique fluorogenic substrate in the presence or absence of the HDAC inhibitor, PBA (A), BS (B), TSA (C) or VAL (D), at different doses. The system’s fluorescence intensity was measured using a fluorescence reader after adding Lysine Developer. Data are expressed as mean ± SEM; n = 3; *P < 0.05 vs. the corresponding baseline of each HDAC subtype.
Mentions: We investigated the inhibitory spectrum of PBA, BS, VAL and TSA with regard to individual HDAC2, 4, 7 and 8. All four inhibitors inhibited HDAC2 and 8 (class I) potently, while they differed a lot in regard to HDAC4 and 7 (class IIa) (Fig. 1). Similar to their effects on class I HDACs, VAL and TSA also robustly inhibited HDAC4 and 7 (Fig. 1C,D). In contrast, PBA and BS had modest or even no obvious inhibitory effect on these class IIa HDACs (Fig. 1A,B), although toxic doses of PBA (>25 mM) significantly inhibited them. Because it has been proposed that activation of class I members is pro-hypertrophic, while activation of class IIa suppresses cardiac hypertrophy1215161718, we postulated that PBA should have a more potent anti-hypertrophic effect than nonselective HDAC inhibitors. Thus, we next determined the role of PBA in pressure overload-induced cardiac remodelling.

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