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

Cardiovascular Diabetology

Original Investigation

Yuan Zhang¹  Darren J Kelly¹  Kerri Thai²  Suzanne L Advani²  Antoinette Bugyei-Twum³  Andrew Advani³  Kim A Connelly⁴ 

[1] Department of Medicine, University of Melbourne St. Vincent’s Hospital, Melbourne, Victoria, Australia;Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, 209 Victoria Street, M5B 1T8, Toronto, ON, Canada;Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, 209 Victoria Street, M5B 1T8, Toronto, ON, Canada;Institute of Medical Science, University of Toronto, 1 King’s College Circle, M5S 1A8, Toronto, ON, Canada;Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, 209 Victoria Street, M5B 1T8, Toronto, ON, Canada;Institute of Medical Science, University of Toronto, 1 King’s College Circle, M5S 1A8, Toronto, ON, Canada;Division of Cardiology, St. Michael’s Hospital, 30 Bond St, Rm 7-052, M5B 1W8, Toronto, ON, Canada;

关键词: Curcumin;    High Glucose;    P300 Activity;    H9c2 Cell;    Heart Failure With Preserve Ejection Fraction;   

DOI  :  10.1186/1475-2840-13-89

 received in 2013-11-13, accepted in 2014-04-23,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundDespite 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 reduced and heart failure prevented in a clinically relevant animal model of diabetic cardiomyopathy.Methodsp300 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-β 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.ResultsIn vitro, H9c2 cells exposed to HG demonstrated increased p300 activity, Smad2 acetylation and increased TGF-β activity as assessed by Smad7 induction (all p < 0.05 c/w NG). Furthermore, HG induced 3H-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-β activity (all p < 0.05 c/w vehicle or scrambled siRNA). Furthermore, curcumin therapy reduced 3H-proline incorporation in HG and TGF-β 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-β activity as assessed by Smad7 activation (all p < 0.05 c/w vehicle treated diabetic animals).ConclusionsThese findings suggest that high glucose increases the activity of the transcriptional co-regulator p300, which increases TGF-β activity via Smad2 acetylation. Modulation of p300 may be a novel strategy to treat diabetes induced heart failure.

【 授权许可】

Unknown   
© Bugyei-Twum et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.