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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 reduced apoptosis in STZ-induced diabetic heart. a Representative Western blots of active caspase-3. b densitometric analysis of active caspase-3 proteins. c Quantitative analysis of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-positive nuclei in myocardium in different groups. d Representative images of TUNEL stainings in myocardial sections. Nuclei were stained in blue (DAPI) and cardiomyocytes in red (α-sarcomeric actinin); TUN EL-positive nuclei were stained in green.α-Sarc Act α-sarcomeric actinin; Values are shown as mean ± SEM (n = 3 per group for Western blots, n = 5 per group for TUNEL); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate. Scale bar 100 µm.
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Fig7: HDAC inhibition reduced apoptosis in STZ-induced diabetic heart. a Representative Western blots of active caspase-3. b densitometric analysis of active caspase-3 proteins. c Quantitative analysis of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-positive nuclei in myocardium in different groups. d Representative images of TUNEL stainings in myocardial sections. Nuclei were stained in blue (DAPI) and cardiomyocytes in red (α-sarcomeric actinin); TUN EL-positive nuclei were stained in green.α-Sarc Act α-sarcomeric actinin; Values are shown as mean ± SEM (n = 3 per group for Western blots, n = 5 per group for TUNEL); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate. Scale bar 100 µm.

Mentions: The apoptotic marker active caspase-3 was examined in the myocardium. As shown in Fig. 7a, active caspase-3 was increased in STZ group as compared with samples from Control groups. Densitometric analysis confirms that the administration of sodium butyrate significantly reduced activated caspase-3 in STZ mice (Fig. 7b). As shown in Fig. 7c, d, TUNEL analysis indicates that STZ-injection increased the number of TUNEL-positive nuclei, but HDAC inhibition reduced apoptotic signals in the diabetic heart.Fig. 7


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 reduced apoptosis in STZ-induced diabetic heart. a Representative Western blots of active caspase-3. b densitometric analysis of active caspase-3 proteins. c Quantitative analysis of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-positive nuclei in myocardium in different groups. d Representative images of TUNEL stainings in myocardial sections. Nuclei were stained in blue (DAPI) and cardiomyocytes in red (α-sarcomeric actinin); TUN EL-positive nuclei were stained in green.α-Sarc Act α-sarcomeric actinin; Values are shown as mean ± SEM (n = 3 per group for Western blots, n = 5 per group for TUNEL); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate. Scale bar 100 µm.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4527099&req=5

Fig7: HDAC inhibition reduced apoptosis in STZ-induced diabetic heart. a Representative Western blots of active caspase-3. b densitometric analysis of active caspase-3 proteins. c Quantitative analysis of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-positive nuclei in myocardium in different groups. d Representative images of TUNEL stainings in myocardial sections. Nuclei were stained in blue (DAPI) and cardiomyocytes in red (α-sarcomeric actinin); TUN EL-positive nuclei were stained in green.α-Sarc Act α-sarcomeric actinin; Values are shown as mean ± SEM (n = 3 per group for Western blots, n = 5 per group for TUNEL); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate. Scale bar 100 µm.
Mentions: The apoptotic marker active caspase-3 was examined in the myocardium. As shown in Fig. 7a, active caspase-3 was increased in STZ group as compared with samples from Control groups. Densitometric analysis confirms that the administration of sodium butyrate significantly reduced activated caspase-3 in STZ mice (Fig. 7b). As shown in Fig. 7c, d, TUNEL analysis indicates that STZ-injection increased the number of TUNEL-positive nuclei, but HDAC inhibition reduced apoptotic signals in the diabetic heart.Fig. 7

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