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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

Effects of HDAC inhibition on attenuating cardiac remodeling in STZ-induced diabetic heart. a The ratio of heart weight to tibia length. b Representative images of WGA staining in the MI hearts. c Quantitative analysis of myocyte cross-sectional area. Values are shown as mean ± SEM (n = 5 per group); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate. Scale bar 100 µm.
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Fig3: Effects of HDAC inhibition on attenuating cardiac remodeling in STZ-induced diabetic heart. a The ratio of heart weight to tibia length. b Representative images of WGA staining in the MI hearts. c Quantitative analysis of myocyte cross-sectional area. Values are shown as mean ± SEM (n = 5 per group); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate. Scale bar 100 µm.

Mentions: The ratio of heart weight to tibia length was used to evaluate the hypertrophic response. STZ injection resulted in an increase in the heart weight/tibia length ratio as compared to control hearts. Treatment of STZ mice with sodium butyrate significantly reduced the heart weight/tibia length ratio (Fig. 3a). In addition, STZ treatment caused a significant increase in heart weight/body weight ratios (Additional file 1: Table S2), which was prevented by treatment with sodium butyrate. STZ-induced diabetic mice WGA staining was performed to access the cross sectional cardiomyocyte size. As shown in Figs. 3b, c, the STZ-treated mice showed an increase in cross-sectional cardiomyocyte diameters as compared with control groups. However, the cross-sectional cardiomyocyte diameter was significantly reduced in STZ mice receiving sodium butyrate as compared with STZ mice only (Fig. 3c). As shown in Fig. 4a, b, the collagen content was significantly increased in STZ group as compared with control groups, but administration of sodium butyrate led to a reduction in interstitial collagen deposition in the myocardium as compared with STZ-treated mice alone although there is no statistically difference between the two diabetic groups.Fig. 3


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)

Effects of HDAC inhibition on attenuating cardiac remodeling in STZ-induced diabetic heart. a The ratio of heart weight to tibia length. b Representative images of WGA staining in the MI hearts. c Quantitative analysis of myocyte cross-sectional area. Values are shown as mean ± SEM (n = 5 per group); *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

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4527099&req=5

Fig3: Effects of HDAC inhibition on attenuating cardiac remodeling in STZ-induced diabetic heart. a The ratio of heart weight to tibia length. b Representative images of WGA staining in the MI hearts. c Quantitative analysis of myocyte cross-sectional area. Values are shown as mean ± SEM (n = 5 per group); *p < 0.05 vs CTRL, #p < 0.05 vs STZ+ NaBu. NaBu sodium butyrate. Scale bar 100 µm.
Mentions: The ratio of heart weight to tibia length was used to evaluate the hypertrophic response. STZ injection resulted in an increase in the heart weight/tibia length ratio as compared to control hearts. Treatment of STZ mice with sodium butyrate significantly reduced the heart weight/tibia length ratio (Fig. 3a). In addition, STZ treatment caused a significant increase in heart weight/body weight ratios (Additional file 1: Table S2), which was prevented by treatment with sodium butyrate. STZ-induced diabetic mice WGA staining was performed to access the cross sectional cardiomyocyte size. As shown in Figs. 3b, c, the STZ-treated mice showed an increase in cross-sectional cardiomyocyte diameters as compared with control groups. However, the cross-sectional cardiomyocyte diameter was significantly reduced in STZ mice receiving sodium butyrate as compared with STZ mice only (Fig. 3c). As shown in Fig. 4a, b, the collagen content was significantly increased in STZ group as compared with control groups, but administration of sodium butyrate led to a reduction in interstitial collagen deposition in the myocardium as compared with STZ-treated mice alone although there is no statistically difference between the two diabetic groups.Fig. 3

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