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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

Time course results of echocardiographic examination of pressure-overloaded mice treated with PBA.(A) Representative pictures of M-mode echocardiography. (B) Left ventricular end-diastolic diameter (LVEDD). (C) Left ventricular end-systolic diameter (LVESD). (D) Left ventricular ejection fraction (LVEF). (E) Left ventricular fractional shortening (LVFS). Sham (n = 10), Sham + PBA (n = 10), TAC (n = 14 at 2 w, n = 10 at 4 w and n = 7 at 6 w) and TAC + PBA (n = 20 at 2 w, n = 12 at 4 w and n = 6 at 6 w). Data are expressed as mean ± SEM. *P < 0.05 vs. the values of the same time point of the TAC group. TAC, transverse aortic constriction.
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f3: Time course results of echocardiographic examination of pressure-overloaded mice treated with PBA.(A) Representative pictures of M-mode echocardiography. (B) Left ventricular end-diastolic diameter (LVEDD). (C) Left ventricular end-systolic diameter (LVESD). (D) Left ventricular ejection fraction (LVEF). (E) Left ventricular fractional shortening (LVFS). Sham (n = 10), Sham + PBA (n = 10), TAC (n = 14 at 2 w, n = 10 at 4 w and n = 7 at 6 w) and TAC + PBA (n = 20 at 2 w, n = 12 at 4 w and n = 6 at 6 w). Data are expressed as mean ± SEM. *P < 0.05 vs. the values of the same time point of the TAC group. TAC, transverse aortic constriction.

Mentions: In a time course experiment, we noted a marked LV chamber dilation (Fig. 3A–C), and a significant decrease in both LV fractional shortening (LVFS) and the LV ejection fraction (LVEF) over time in the PBA (100 mg/kg/d)-treated TAC mice (Fig. 3D,E) compared with the untreated TAC mice. In contrast, there were no significant differences in these parameters between PBA-treated and untreated sham mice. These findings indicate that the increase in cardiac remodelling under pressure overload was promoted by PBA.


Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition
Time course results of echocardiographic examination of pressure-overloaded mice treated with PBA.(A) Representative pictures of M-mode echocardiography. (B) Left ventricular end-diastolic diameter (LVEDD). (C) Left ventricular end-systolic diameter (LVESD). (D) Left ventricular ejection fraction (LVEF). (E) Left ventricular fractional shortening (LVFS). Sham (n = 10), Sham + PBA (n = 10), TAC (n = 14 at 2 w, n = 10 at 4 w and n = 7 at 6 w) and TAC + PBA (n = 20 at 2 w, n = 12 at 4 w and n = 6 at 6 w). Data are expressed as mean ± SEM. *P < 0.05 vs. the values of the same time point of the TAC group. TAC, transverse aortic constriction.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Time course results of echocardiographic examination of pressure-overloaded mice treated with PBA.(A) Representative pictures of M-mode echocardiography. (B) Left ventricular end-diastolic diameter (LVEDD). (C) Left ventricular end-systolic diameter (LVESD). (D) Left ventricular ejection fraction (LVEF). (E) Left ventricular fractional shortening (LVFS). Sham (n = 10), Sham + PBA (n = 10), TAC (n = 14 at 2 w, n = 10 at 4 w and n = 7 at 6 w) and TAC + PBA (n = 20 at 2 w, n = 12 at 4 w and n = 6 at 6 w). Data are expressed as mean ± SEM. *P < 0.05 vs. the values of the same time point of the TAC group. TAC, transverse aortic constriction.
Mentions: In a time course experiment, we noted a marked LV chamber dilation (Fig. 3A–C), and a significant decrease in both LV fractional shortening (LVFS) and the LV ejection fraction (LVEF) over time in the PBA (100 mg/kg/d)-treated TAC mice (Fig. 3D,E) compared with the untreated TAC mice. In contrast, there were no significant differences in these parameters between PBA-treated and untreated sham mice. These findings indicate that the increase in cardiac remodelling under pressure overload was promoted by PBA.

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