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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

Results of left ventricular haemodynamics 6 weeks after surgery.(A) Representative recording curves of left ventricular pressure (LVP). (B) Left ventricular end-diastolic pressure (LVEDP). (C) The maximum rising rate of LVP (dP/dt max). (D) The maximum fall rate of LVP (dP/dt min). (E) LV contractility index. (F) The exponential time constant of relaxation (tau). Data are expressed as mean ± SEM. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. Sham + Veh (n = 7); Sham + PBA (100 mg/kg/d, ip, n = 6); TAC (n = 9); TAC + PBA (100 mg/kg/d, ip, n = 12). TAC, transverse aortic constriction; Veh, vehicle.
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f4: Results of left ventricular haemodynamics 6 weeks after surgery.(A) Representative recording curves of left ventricular pressure (LVP). (B) Left ventricular end-diastolic pressure (LVEDP). (C) The maximum rising rate of LVP (dP/dt max). (D) The maximum fall rate of LVP (dP/dt min). (E) LV contractility index. (F) The exponential time constant of relaxation (tau). Data are expressed as mean ± SEM. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. Sham + Veh (n = 7); Sham + PBA (100 mg/kg/d, ip, n = 6); TAC (n = 9); TAC + PBA (100 mg/kg/d, ip, n = 12). TAC, transverse aortic constriction; Veh, vehicle.

Mentions: Six weeks after surgery, the LV systolic pressure was similar in PBA-treated and untreated TAC mice. However, both the LV end-diastolic pressure (LVEDP) and Tau were significantly larger, and the ± dP/dt max and LV contractility index were significantly lower in PBA (100 mg/kg/d)-treated TAC mice than in the vehicle-treated group (Fig. 4A–F, Table 1). No significant change was found in the PBA-treated sham mice (Table 1). These results suggest that PBA worsened both the systolic and diastolic function in TAC mice.


Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition
Results of left ventricular haemodynamics 6 weeks after surgery.(A) Representative recording curves of left ventricular pressure (LVP). (B) Left ventricular end-diastolic pressure (LVEDP). (C) The maximum rising rate of LVP (dP/dt max). (D) The maximum fall rate of LVP (dP/dt min). (E) LV contractility index. (F) The exponential time constant of relaxation (tau). Data are expressed as mean ± SEM. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. Sham + Veh (n = 7); Sham + PBA (100 mg/kg/d, ip, n = 6); TAC (n = 9); TAC + PBA (100 mg/kg/d, ip, n = 12). TAC, transverse aortic constriction; Veh, vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036044&req=5

f4: Results of left ventricular haemodynamics 6 weeks after surgery.(A) Representative recording curves of left ventricular pressure (LVP). (B) Left ventricular end-diastolic pressure (LVEDP). (C) The maximum rising rate of LVP (dP/dt max). (D) The maximum fall rate of LVP (dP/dt min). (E) LV contractility index. (F) The exponential time constant of relaxation (tau). Data are expressed as mean ± SEM. *P < 0.05 vs. the Sham group, †P < 0.05 vs. the TAC group. Sham + Veh (n = 7); Sham + PBA (100 mg/kg/d, ip, n = 6); TAC (n = 9); TAC + PBA (100 mg/kg/d, ip, n = 12). TAC, transverse aortic constriction; Veh, vehicle.
Mentions: Six weeks after surgery, the LV systolic pressure was similar in PBA-treated and untreated TAC mice. However, both the LV end-diastolic pressure (LVEDP) and Tau were significantly larger, and the ± dP/dt max and LV contractility index were significantly lower in PBA (100 mg/kg/d)-treated TAC mice than in the vehicle-treated group (Fig. 4A–F, Table 1). No significant change was found in the PBA-treated sham mice (Table 1). These results suggest that PBA worsened both the systolic and diastolic function in TAC mice.

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