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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.


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PBA increases mortality and pulmonary congestion in mice with TAC surgery.(A) Kaplan–Meier analysis of the mortality rate of TAC mice treated with or without PBA (100 mg/kg/d, ip, for 6 weeks). (B) Representative pictures of the lungs. (C) Lung weight (LW) to body weight (BW). Scale bar: 2 mm. Data are expressed as mean ± SEM. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. TAC group (n = 22), TAC + PBA group (n = 22), Sham group (n = 8), Sham + PBA group (n = 8). TAC, transverse aortic constriction.
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f5: PBA increases mortality and pulmonary congestion in mice with TAC surgery.(A) Kaplan–Meier analysis of the mortality rate of TAC mice treated with or without PBA (100 mg/kg/d, ip, for 6 weeks). (B) Representative pictures of the lungs. (C) Lung weight (LW) to body weight (BW). Scale bar: 2 mm. Data are expressed as mean ± SEM. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. TAC group (n = 22), TAC + PBA group (n = 22), Sham group (n = 8), Sham + PBA group (n = 8). TAC, transverse aortic constriction.

Mentions: In response to high-pressure overload, some mice died of severe acute or chronic heart failure. Lung haemorrhage or pleural effusion was also seen in some cases. Kaplan–Meier analysis revealed that the survival rate of vehicle-treated TAC mice was 66.7% at 6 weeks after surgery, while it was only 32.7% in the PBA-treated (100 mg/kg/d) group (P < 0.01, Fig. 5A).


Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition
PBA increases mortality and pulmonary congestion in mice with TAC surgery.(A) Kaplan–Meier analysis of the mortality rate of TAC mice treated with or without PBA (100 mg/kg/d, ip, for 6 weeks). (B) Representative pictures of the lungs. (C) Lung weight (LW) to body weight (BW). Scale bar: 2 mm. Data are expressed as mean ± SEM. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. TAC group (n = 22), TAC + PBA group (n = 22), Sham group (n = 8), Sham + PBA group (n = 8). TAC, transverse aortic constriction.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: PBA increases mortality and pulmonary congestion in mice with TAC surgery.(A) Kaplan–Meier analysis of the mortality rate of TAC mice treated with or without PBA (100 mg/kg/d, ip, for 6 weeks). (B) Representative pictures of the lungs. (C) Lung weight (LW) to body weight (BW). Scale bar: 2 mm. Data are expressed as mean ± SEM. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. TAC group (n = 22), TAC + PBA group (n = 22), Sham group (n = 8), Sham + PBA group (n = 8). TAC, transverse aortic constriction.
Mentions: In response to high-pressure overload, some mice died of severe acute or chronic heart failure. Lung haemorrhage or pleural effusion was also seen in some cases. Kaplan–Meier analysis revealed that the survival rate of vehicle-treated TAC mice was 66.7% at 6 weeks after surgery, while it was only 32.7% in the PBA-treated (100 mg/kg/d) group (P < 0.01, Fig. 5A).

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