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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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The effects of different HDAC inhibitors on TAC-induced mortality.(A) The chemical structures of the HDAC inhibitors, PBA, BS, TSA and VAL. (B) Kaplan–Meier analysis of the mortality rate of mice subjected to TAC surgery with or without HDAC inhibitor treatment for 6 weeks, including PBA (100 mg/kg/d, ip), BS (100 mg/kg/d, ip), TSA (0.6 mg/kg/d, ip) and VAL (0.71% in drinking water). (C) Western blots of H3 acetylation. (D) Representative image of whole hearts (left panel), and ratio of heart weight (HW) to body weight (BW) (right panel) of the TAC mice with or without low-dose PBA treatment (10 mg/kg/d, ip, for 6 weeks). Data are expressed as mean ± SEM. Sham + Veh (n = 4); Sham + PBA (10 mg/kg/d, ip, n = 4); TAC (n = 6); TAC + PBA (10 mg/kg/d, ip, n = 6). PBA (1), PBA 10 mg/kg/d; TAC, transverse aortic constriction.
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f7: The effects of different HDAC inhibitors on TAC-induced mortality.(A) The chemical structures of the HDAC inhibitors, PBA, BS, TSA and VAL. (B) Kaplan–Meier analysis of the mortality rate of mice subjected to TAC surgery with or without HDAC inhibitor treatment for 6 weeks, including PBA (100 mg/kg/d, ip), BS (100 mg/kg/d, ip), TSA (0.6 mg/kg/d, ip) and VAL (0.71% in drinking water). (C) Western blots of H3 acetylation. (D) Representative image of whole hearts (left panel), and ratio of heart weight (HW) to body weight (BW) (right panel) of the TAC mice with or without low-dose PBA treatment (10 mg/kg/d, ip, for 6 weeks). Data are expressed as mean ± SEM. Sham + Veh (n = 4); Sham + PBA (10 mg/kg/d, ip, n = 4); TAC (n = 6); TAC + PBA (10 mg/kg/d, ip, n = 6). PBA (1), PBA 10 mg/kg/d; TAC, transverse aortic constriction.

Mentions: The chemical structure of PBA, BS, TSA and VAL is shown in Fig. 7A. Interestingly, BS also significantly increased the mortality of TAC mice. The survival rate was similar to that of PBA-treated TAC mice (30.8% vs. 32.7%, Fig. 7B). In contrast, either VAL or TSA treatment significantly improved the survival rate of TAC mice, which is in good agreement with previous reports1213.


Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition
The effects of different HDAC inhibitors on TAC-induced mortality.(A) The chemical structures of the HDAC inhibitors, PBA, BS, TSA and VAL. (B) Kaplan–Meier analysis of the mortality rate of mice subjected to TAC surgery with or without HDAC inhibitor treatment for 6 weeks, including PBA (100 mg/kg/d, ip), BS (100 mg/kg/d, ip), TSA (0.6 mg/kg/d, ip) and VAL (0.71% in drinking water). (C) Western blots of H3 acetylation. (D) Representative image of whole hearts (left panel), and ratio of heart weight (HW) to body weight (BW) (right panel) of the TAC mice with or without low-dose PBA treatment (10 mg/kg/d, ip, for 6 weeks). Data are expressed as mean ± SEM. Sham + Veh (n = 4); Sham + PBA (10 mg/kg/d, ip, n = 4); TAC (n = 6); TAC + PBA (10 mg/kg/d, ip, n = 6). PBA (1), PBA 10 mg/kg/d; TAC, transverse aortic constriction.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036044&req=5

f7: The effects of different HDAC inhibitors on TAC-induced mortality.(A) The chemical structures of the HDAC inhibitors, PBA, BS, TSA and VAL. (B) Kaplan–Meier analysis of the mortality rate of mice subjected to TAC surgery with or without HDAC inhibitor treatment for 6 weeks, including PBA (100 mg/kg/d, ip), BS (100 mg/kg/d, ip), TSA (0.6 mg/kg/d, ip) and VAL (0.71% in drinking water). (C) Western blots of H3 acetylation. (D) Representative image of whole hearts (left panel), and ratio of heart weight (HW) to body weight (BW) (right panel) of the TAC mice with or without low-dose PBA treatment (10 mg/kg/d, ip, for 6 weeks). Data are expressed as mean ± SEM. Sham + Veh (n = 4); Sham + PBA (10 mg/kg/d, ip, n = 4); TAC (n = 6); TAC + PBA (10 mg/kg/d, ip, n = 6). PBA (1), PBA 10 mg/kg/d; TAC, transverse aortic constriction.
Mentions: The chemical structure of PBA, BS, TSA and VAL is shown in Fig. 7A. Interestingly, BS also significantly increased the mortality of TAC mice. The survival rate was similar to that of PBA-treated TAC mice (30.8% vs. 32.7%, Fig. 7B). In contrast, either VAL or TSA treatment significantly improved the survival rate of TAC mice, which is in good agreement with previous reports1213.

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