Dataset Information

High glucose induces Smad activation via the transcriptional coregulator p300 and contributes to cardiac fibrosis and hypertrophy.

ABSTRACT:

Background

Despite advances in the treatment of heart failure, mortality remains high, particularly in individuals with diabetes. Activated transforming growth factor beta (TGF-?) 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-? via acetylation of Smad2; and that by inhibiting p300, TGF-? 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. 3H-proline incorporation in cardiac fibroblasts was also assessed as a marker of collagen synthesis. The role of p300 activity in modifying TGF-? 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-? activity as assessed by Smad7 induction (all p ConclusionsThese findings suggest that high glucose increases the activity of the transcriptional co-regulator p300, which increases TGF-? activity via Smad2 acetylation. Modulation of p300 may be a novel strategy to treat diabetes induced heart failure.

SUBMITTER: Bugyei-Twum A

PROVIDER: S-EPMC4108062 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Publications

High glucose induces Smad activation via the transcriptional coregulator p300 and contributes to cardiac fibrosis and hypertrophy.

Bugyei-Twum Antoinette A Advani Andrew A Advani Suzanne L SL Zhang Yuan Y Thai Kerri K Kelly Darren J DJ Connelly Kim A KA

Cardiovascular diabetology 20140505

<h4>Background</h4>Despite advances in the treatment of heart failure, mortality remains high, particularly in individuals with diabetes. Activated transforming growth factor beta (TGF-β) 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-β via acetylation of Smad2; and that by inhibiting p300, TGF-β activity will be red ...[more]

PMID: 24886336

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Dataset Information

High glucose induces Smad activation via the transcriptional coregulator p300 and contributes to cardiac fibrosis and hypertrophy.

Background

Methods

Results

Publications

High glucose induces Smad activation via the transcriptional coregulator p300 and contributes to cardiac fibrosis and hypertrophy.

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