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Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice.

Chen Y, Du J, Zhao YT, Zhang L, Lv G, Zhuang S, Qin G, Zhao TC - Cardiovasc Diabetol (2015)

Bottom Line: However, it remains unknown whether HDAC inhibition produces the protective effect in the diabetic heart.Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes, which is associated with reduced interstitial fibrosis and decreases in active caspase-3 and apoptotic stainings, but also increased angiogenesis in diabetic myocardium.HDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Boston University, 50 Maude Street, Providence, RI, 02908, USA. cyf988@126.com.

ABSTRACT

Background: Recent evidence indicates that inhibition of histone deacetylase (HDAC) protects the heart against myocardial injury and stimulates endogenous angiomyogenesis. However, it remains unknown whether HDAC inhibition produces the protective effect in the diabetic heart. We sought to determine whether HDAC inhibition preserves cardiac performance and suppresses cardiac remodeling in diabetic cardiomyopathy.

Methods: Adult ICR mice received an intraperitoneal injection of either streptozotocin (STZ, 200 mg/kg) to establish the diabetic model or vehicle to serve as control. Once hyperglycemia was confirmed, diabetic mice received sodium butyrate (1%), a specific HDAC inhibitor, in drinking water on a daily basis to inhibit HDAC activity. Mice were randomly divided into following groups, which includes Control, Control + Sodium butyrate (NaBu), STZ and STZ + Sodium butyrate (NaBu), respectively. Myocardial function was serially assessed at 7, 14, 21 weeks following treatments.

Results: Echocardiography demonstrated that cardiac function was depressed in diabetic mice, but HDAC inhibition resulted in a significant functional improvement in STZ-injected mice. Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes, which is associated with reduced interstitial fibrosis and decreases in active caspase-3 and apoptotic stainings, but also increased angiogenesis in diabetic myocardium. Notably, glucose transporters (GLUT) 1 and 4 were up-regulated following HDAC inhibition, which was accompanied with increases of GLUT1 acetylation and p38 phosphorylation. Furthermore, myocardial superoxide dismutase, an important antioxidant, was elevated following HDAC inhibition in the diabetic mice.

Conclusion: HDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart.

No MeSH data available.


Related in: MedlinePlus

HDAC inhibition increased p38 phosphorylation in diabetic myocardium. a Representative Western blot showing phosphorylated p38 and p38 proteins. b Densitometric analysis of phosphorylated p38 protein level in different groups. The densitometric signal was normalized to the control group and expressed as a percentage. Values are shown as mean ± SEM (n = 3 per group); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate.
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Fig6: HDAC inhibition increased p38 phosphorylation in diabetic myocardium. a Representative Western blot showing phosphorylated p38 and p38 proteins. b Densitometric analysis of phosphorylated p38 protein level in different groups. The densitometric signal was normalized to the control group and expressed as a percentage. Values are shown as mean ± SEM (n = 3 per group); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate.

Mentions: When we measured HDAC activity in the diabetic myocardium, HDAC activity demonstrated an increase in STZ-induced diabetic heart, but HDAC activity was significantly reduced following the treatment of animals with sodium butyrate (Fig. 5a). In addition, as shown in Fig. 5b, c, treatment of mice with sodium butyrate decreased the expression level of HDAC4 in both Control and STZ-treated groups. Other HDAC isoforms were not changed in the diabetic myocardium between groups (Additional file 1: Figure. S1). The glucose transporter signaling pathway was further confirmed. As shown in Fig. 5d–g, STZ induced a down-regulation of GLUT1 and GLUT4 protein levels in STZ heart as compared with Control groups. However, HDAC inhibition resulted in up-regulations in both GLUT4 and GLUT1 in STZ heart, which restored the signal to the same level as the control group. Notably, GLUT1 was subjected to regulation by acetylation. As shown in Fig. 5h, HDAC inhibition increased the level of acetylated GLUT1 in sodium butyrate-treated STZ mice as compared with STZ alone. However, HDAC inhibition did not result in a significant increase in acetylated GLUT4 although we noted there was a detectable level of acetylated GLUT4. Interestingly, as shown in Fig. 6, we found that the diabetic myocardium demonstrated a decrease in phosphorylated p38 level, but HDAC inhibition resulted in a significant increase in phosphorylation of p38.Fig. 5


Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice.

Chen Y, Du J, Zhao YT, Zhang L, Lv G, Zhuang S, Qin G, Zhao TC - Cardiovasc Diabetol (2015)

HDAC inhibition increased p38 phosphorylation in diabetic myocardium. a Representative Western blot showing phosphorylated p38 and p38 proteins. b Densitometric analysis of phosphorylated p38 protein level in different groups. The densitometric signal was normalized to the control group and expressed as a percentage. Values are shown as mean ± SEM (n = 3 per group); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4527099&req=5

Fig6: HDAC inhibition increased p38 phosphorylation in diabetic myocardium. a Representative Western blot showing phosphorylated p38 and p38 proteins. b Densitometric analysis of phosphorylated p38 protein level in different groups. The densitometric signal was normalized to the control group and expressed as a percentage. Values are shown as mean ± SEM (n = 3 per group); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate.
Mentions: When we measured HDAC activity in the diabetic myocardium, HDAC activity demonstrated an increase in STZ-induced diabetic heart, but HDAC activity was significantly reduced following the treatment of animals with sodium butyrate (Fig. 5a). In addition, as shown in Fig. 5b, c, treatment of mice with sodium butyrate decreased the expression level of HDAC4 in both Control and STZ-treated groups. Other HDAC isoforms were not changed in the diabetic myocardium between groups (Additional file 1: Figure. S1). The glucose transporter signaling pathway was further confirmed. As shown in Fig. 5d–g, STZ induced a down-regulation of GLUT1 and GLUT4 protein levels in STZ heart as compared with Control groups. However, HDAC inhibition resulted in up-regulations in both GLUT4 and GLUT1 in STZ heart, which restored the signal to the same level as the control group. Notably, GLUT1 was subjected to regulation by acetylation. As shown in Fig. 5h, HDAC inhibition increased the level of acetylated GLUT1 in sodium butyrate-treated STZ mice as compared with STZ alone. However, HDAC inhibition did not result in a significant increase in acetylated GLUT4 although we noted there was a detectable level of acetylated GLUT4. Interestingly, as shown in Fig. 6, we found that the diabetic myocardium demonstrated a decrease in phosphorylated p38 level, but HDAC inhibition resulted in a significant increase in phosphorylation of p38.Fig. 5

Bottom Line: However, it remains unknown whether HDAC inhibition produces the protective effect in the diabetic heart.Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes, which is associated with reduced interstitial fibrosis and decreases in active caspase-3 and apoptotic stainings, but also increased angiogenesis in diabetic myocardium.HDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Boston University, 50 Maude Street, Providence, RI, 02908, USA. cyf988@126.com.

ABSTRACT

Background: Recent evidence indicates that inhibition of histone deacetylase (HDAC) protects the heart against myocardial injury and stimulates endogenous angiomyogenesis. However, it remains unknown whether HDAC inhibition produces the protective effect in the diabetic heart. We sought to determine whether HDAC inhibition preserves cardiac performance and suppresses cardiac remodeling in diabetic cardiomyopathy.

Methods: Adult ICR mice received an intraperitoneal injection of either streptozotocin (STZ, 200 mg/kg) to establish the diabetic model or vehicle to serve as control. Once hyperglycemia was confirmed, diabetic mice received sodium butyrate (1%), a specific HDAC inhibitor, in drinking water on a daily basis to inhibit HDAC activity. Mice were randomly divided into following groups, which includes Control, Control + Sodium butyrate (NaBu), STZ and STZ + Sodium butyrate (NaBu), respectively. Myocardial function was serially assessed at 7, 14, 21 weeks following treatments.

Results: Echocardiography demonstrated that cardiac function was depressed in diabetic mice, but HDAC inhibition resulted in a significant functional improvement in STZ-injected mice. Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes, which is associated with reduced interstitial fibrosis and decreases in active caspase-3 and apoptotic stainings, but also increased angiogenesis in diabetic myocardium. Notably, glucose transporters (GLUT) 1 and 4 were up-regulated following HDAC inhibition, which was accompanied with increases of GLUT1 acetylation and p38 phosphorylation. Furthermore, myocardial superoxide dismutase, an important antioxidant, was elevated following HDAC inhibition in the diabetic mice.

Conclusion: HDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart.

No MeSH data available.


Related in: MedlinePlus