期刊
CARDIOVASCULAR DIABETOLOGY
卷 13, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/1475-2840-13-89
关键词
-
资金
- Heart and Stroke Foundation of Canada [NA 7201]
- CIHR Strategic Training Fellowship [TGF-53877]
Background: Despite advances in the treatment of heart failure, mortality remains high, particularly in individuals with diabetes. Activated transforming growth factor beta (TGF-beta) contributes to the pathogenesis of the fibrotic interstitium observed in diabetic cardiomyopathy. We hypothesized that high glucose enhances the activity of the transcriptional co-activator p300, leading to the activation of TGF-beta via acetylation of Smad2; and that by inhibiting p300, TGF-beta activity will be reduced and heart failure prevented in a clinically relevant animal model of diabetic cardiomyopathy. Methods: p300 activity was assessed in H9c2 cardiomyoblasts under normal glucose (5.6 mmol/L-NG) and high glucose (25 mmol/L-HG) conditions. H-3-proline incorporation in cardiac fibroblasts was also assessed as a marker of collagen synthesis. The role of p300 activity in modifying TGF-beta activity was investigated with a known p300 inhibitor, curcumin or p300 siRNA in vitro, and the functional effects of p300 inhibition were assessed using curcumin in a hemodynamically validated model of diabetic cardiomyopathy - the diabetic TG m(Ren-2)27 rat. Results: In vitro, H9c2 cells exposed to HG demonstrated increased p300 activity, Smad2 acetylation and increased TGF-beta activity as assessed by Smad7 induction (all p < 0.05 c/w NG). Furthermore, HG induced H-3-proline incorporation as a marker of collagen synthesis (p < 0.05 c/w NG). p300 inhibition, using either siRNA or curcumin reduced p300 activity, Smad acetylation and TGF-beta activity (all p < 0.05 c/w vehicle or scrambled siRNA). Furthermore, curcumin therapy reduced H-3-proline incorporation in HG and TGF-beta stimulated fibroblasts (p < 0.05 c/w NG). To determine the functional significance of p300 inhibition, diabetic Ren-2 rats were randomized to receive curcumin or vehicle for 6 weeks. Curcumin treatment reduced cardiac hypertrophy, improved diastolic function and reduced extracellular matrix production, without affecting glycemic control, along with a reduction in TGF-beta activity as assessed by Smad7 activation (all p < 0.05 c/w vehicle treated diabetic animals). Conclusions: These findings suggest that high glucose increases the activity of the transcriptional co-regulator p300, which increases TGF-beta activity via Smad2 acetylation. Modulation of p300 may be a novel strategy to treat diabetes induced heart failure.
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