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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

Effects of PBA on cardiac hypertrophy induced by pressure overload in mice.(A) Representative recording curves of blood pressure (BP). (B) Statistical results of systolic BP (SBP) recorded from the right carotid artery by invasive cannulation with a Millar Pressure Catheter in mice subjected to sham or TAC operation with or without PBA treatment (100 mg/kg/d, ip, for 6 weeks). 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). (C) Representative images of whole hearts. (D) Whole view of heart cross sections stained with haematoxylin–eosin. (E) Cross-axis view of cardiomyocytes. (F) Long-axis view of cardiomyocytes. Scale = 20 μm in D and E. (G) The ratio of heart weight (HW) to body weight (BW). (H) Cardiomyocyte cross-sectional area. In (G) TAC group (n = 22), TAC + PBA group (n = 22), Sham group (n = 8), Sham + PBA group (n = 8). In (H) four mice in each group were selected and 400 cardiomyocytes per animal were chosen randomly. Data are expressed as mean ± SEM. *P < 0.05. NS, not significant; TAC, transverse aortic constriction; Veh, vehicle.
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f2: Effects of PBA on cardiac hypertrophy induced by pressure overload in mice.(A) Representative recording curves of blood pressure (BP). (B) Statistical results of systolic BP (SBP) recorded from the right carotid artery by invasive cannulation with a Millar Pressure Catheter in mice subjected to sham or TAC operation with or without PBA treatment (100 mg/kg/d, ip, for 6 weeks). 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). (C) Representative images of whole hearts. (D) Whole view of heart cross sections stained with haematoxylin–eosin. (E) Cross-axis view of cardiomyocytes. (F) Long-axis view of cardiomyocytes. Scale = 20 μm in D and E. (G) The ratio of heart weight (HW) to body weight (BW). (H) Cardiomyocyte cross-sectional area. In (G) TAC group (n = 22), TAC + PBA group (n = 22), Sham group (n = 8), Sham + PBA group (n = 8). In (H) four mice in each group were selected and 400 cardiomyocytes per animal were chosen randomly. Data are expressed as mean ± SEM. *P < 0.05. NS, not significant; TAC, transverse aortic constriction; Veh, vehicle.

Mentions: The systolic blood pressure of the aorta in both the TAC and TAC + PBA (100 mg/kg/d) groups reached about 200 mmHg (Fig. 2A,B), indicating that similar pressure overload between the two groups was achieved. Six weeks later, TAC resulted in a significant increase in whole heart size (Fig. 2C), left ventricular (LV) wall thickness (Fig. 2D), cross section area of LV cardiomyocytes (Fig. 2E) and muscle bundle size of LV myocardium (Fig. 2F). Compared with the Sham group, a 90% increase in the heart weight/body weight (HW/BW) ratio (Fig. 2G) and a marked enlarged cross-sectional surface area of cardiomyocytes were noted in the TAC group (Fig. 2H). Unexpectedly, PBA treatment further amplified the cardiac hypertrophy (Fig. 2C–H). The HW/BW ratio increased to 138% of the sham mice (Fig. 2G), which was also evidenced by histological findings (Fig. 2H). There were no significant differences in the HW/BW ratio and the cardiomyocyte cross-sectional surface area between PBA-treated and untreated sham mice.


Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition
Effects of PBA on cardiac hypertrophy induced by pressure overload in mice.(A) Representative recording curves of blood pressure (BP). (B) Statistical results of systolic BP (SBP) recorded from the right carotid artery by invasive cannulation with a Millar Pressure Catheter in mice subjected to sham or TAC operation with or without PBA treatment (100 mg/kg/d, ip, for 6 weeks). 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). (C) Representative images of whole hearts. (D) Whole view of heart cross sections stained with haematoxylin–eosin. (E) Cross-axis view of cardiomyocytes. (F) Long-axis view of cardiomyocytes. Scale = 20 μm in D and E. (G) The ratio of heart weight (HW) to body weight (BW). (H) Cardiomyocyte cross-sectional area. In (G) TAC group (n = 22), TAC + PBA group (n = 22), Sham group (n = 8), Sham + PBA group (n = 8). In (H) four mice in each group were selected and 400 cardiomyocytes per animal were chosen randomly. Data are expressed as mean ± SEM. *P < 0.05. NS, not significant; TAC, transverse aortic constriction; Veh, vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036044&req=5

f2: Effects of PBA on cardiac hypertrophy induced by pressure overload in mice.(A) Representative recording curves of blood pressure (BP). (B) Statistical results of systolic BP (SBP) recorded from the right carotid artery by invasive cannulation with a Millar Pressure Catheter in mice subjected to sham or TAC operation with or without PBA treatment (100 mg/kg/d, ip, for 6 weeks). 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). (C) Representative images of whole hearts. (D) Whole view of heart cross sections stained with haematoxylin–eosin. (E) Cross-axis view of cardiomyocytes. (F) Long-axis view of cardiomyocytes. Scale = 20 μm in D and E. (G) The ratio of heart weight (HW) to body weight (BW). (H) Cardiomyocyte cross-sectional area. In (G) TAC group (n = 22), TAC + PBA group (n = 22), Sham group (n = 8), Sham + PBA group (n = 8). In (H) four mice in each group were selected and 400 cardiomyocytes per animal were chosen randomly. Data are expressed as mean ± SEM. *P < 0.05. NS, not significant; TAC, transverse aortic constriction; Veh, vehicle.
Mentions: The systolic blood pressure of the aorta in both the TAC and TAC + PBA (100 mg/kg/d) groups reached about 200 mmHg (Fig. 2A,B), indicating that similar pressure overload between the two groups was achieved. Six weeks later, TAC resulted in a significant increase in whole heart size (Fig. 2C), left ventricular (LV) wall thickness (Fig. 2D), cross section area of LV cardiomyocytes (Fig. 2E) and muscle bundle size of LV myocardium (Fig. 2F). Compared with the Sham group, a 90% increase in the heart weight/body weight (HW/BW) ratio (Fig. 2G) and a marked enlarged cross-sectional surface area of cardiomyocytes were noted in the TAC group (Fig. 2H). Unexpectedly, PBA treatment further amplified the cardiac hypertrophy (Fig. 2C–H). The HW/BW ratio increased to 138% of the sham mice (Fig. 2G), which was also evidenced by histological findings (Fig. 2H). There were no significant differences in the HW/BW ratio and the cardiomyocyte cross-sectional surface area between PBA-treated and untreated sham 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