Novel Insight Into the Epigenetic and Post-transcriptional Control of Cardiac Gene Expression by Thyroid Hormone

Objective: In view of their different actions on thyroid hormone receptor (TR) isoforms we set out to investigate whether amiodarone (AM) and dronedarone (Dron) have different and/or component-specific effects on cardiac gene expression. Design: Rats were treated with AM or Dron and the expression of TRα 1, TRα 2, TRβ 1 and several tri-iodothyronine (T3)-regulated genes was studied in different parts of the heart, namely the right atrium (RA), left ventricular wall (LVW) and apex. Methods: Rats were treated for 14 days with 100 mg/kg body weight AM or Dron. The expression of TRα 1, TRα 2, TRβ 1 and T3-regulated genes was studied using real-time PCR and non-radioactive in situ hybridisation. Results: AM and Dron affected TR expression in the RA similarly by decreasing TRα 1 and β 1 expression by about 50%. In the LVW, AM and Dron decreased TRβ 1 and, interestingly, AM increased TRα 1. In the apex, AM also increased TRα 2. The changes seen in T3-dependent gene expression are reminiscent of foetal reprogramming. Conclusion: Taken together, our results indicate that AM and Dron have similar effects on the expression of TR isoforms in the RA, which could partly contribute to their ability to decrease heart rate. On the other hand, the more profound effect of AM appears on TR- and T3-dependent gene expression in the left ventricle suggests foetal reprogramming.

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Thyroid Hormone-Regulated Cardiac Gene Expression and Cardiovascular Disease

Thyroid ◽

10.1089/105072502760143836 ◽

2002 ◽

Vol 12 (6) ◽

pp. 467-472 ◽

Cited By ~ 39

Author(s):

Sara Danzi ◽

Irwin Klein

Keyword(s):

Gene Expression ◽

Cardiovascular Disease ◽

Thyroid Hormone ◽

Cardiac Gene Expression ◽

Cardiac Gene

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Doppler Echocardiographic Assessment and Cardiac Gene Expression Analysis of the Left Ventricle in Myocardial lnfarcted Rats

Japanese Circulation Journal ◽

10.1253/jcj.62.436 ◽

1998 ◽

Vol 62 (6) ◽

pp. 436-442 ◽

Cited By ~ 14

Author(s):

Naruhito Shimizu ◽

Minoru Yoshiyama ◽

Kazuhide Takeuchi ◽

Akihisa Hanatani ◽

Shokei Kim ◽

...

Keyword(s):

Gene Expression ◽

Left Ventricle ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Cardiac Gene Expression ◽

Cardiac Gene ◽

Echocardiographic Assessment

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Myocardin Marks the Earliest Cardiac Gene Expression and Plays an Important Role in Heart Development

The Anatomical Record ◽

10.1002/ar.20756 ◽

2008 ◽

Vol 291 (10) ◽

pp. 1200-1211 ◽

Cited By ~ 8

Author(s):

Jian-Fu Chen ◽

Shusheng Wang ◽

Qiulian Wu ◽

Dongsun Cao ◽

Thiha Nguyen ◽

...

Keyword(s):

Gene Expression ◽

Heart Development ◽

Cardiac Gene Expression ◽

Cardiac Gene

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Abstract 247: Scaffold-stiffness Dependent Notch1 Activation Regulates Cardiogenic Gene Expression In Cardiac Progenitor Cells

Circulation Research ◽

10.1161/res.113.suppl_1.a247 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Archana V Boopathy ◽

Pao L Che ◽

Yoshie Narui ◽

Khalid Salaita ◽

Michael E Davis

Keyword(s):

Gene Expression ◽

Smooth Muscle ◽

Cardiac Function ◽

Progenitor Cells ◽

Adult Stem Cells ◽

Cardiac Progenitor Cells ◽

Critical Pathway ◽

Cardiac Gene Expression ◽

Self Assembling ◽

Cardiac Gene

Rationale: Cardiac progenitor cells (CPCs) are multipotent, self-renewing cells that can regenerate the myocardium and improve cardiac function in animal models of myocardial infarction (MI). However, limited survival of stem/progenitor cells inhibits cardiac regeneration. Force dependent Notch activation promotes cardiac development and cardiac gene expression in many adult stem cells. As dysregulation of Notch signaling leads to embryonic lethal cardiovascular defects, activating this critical pathway during cell transplantation could improve efficacy of stem cell therapy. Objective: Investigate i) whether self-assembling peptide scaffolds can be used to activate Notch1 signaling in CPCs to promote cardiogenic differentiation and ii) the effect of scaffold stiffness on Notch1 activation and differentiation. Methods: Rat CPCs (c-kit + ) were cultured for 48h in 3D self-assembling scaffolds of varying stiffness (1% low, 2% high): empty scaffolds (RADA), scaffolds modified with peptide mimicking Notch1 ligand, Jagged1 (RJAG), or scaffolds modified with a scrambled peptide (RSCR) and cardiogenic gene expression measured by qRT-PCR. CHO cells expressing Notch1 responsive YFP were also cultured in the above scaffolds for 48h and YFP expression was determined. Results are mean ± SEM with p<0.05 considered significant by one or two-way ANOVA with appropriate post test. Results: In the Notch1 reporter cells, Notch1 activation increased significantly in presence of RJAG (p<0.01) and on increasing scaffold stiffness (p<0.01,n=6) indicating scaffold stiffness-dependent Notch1 activation. Culture of CPCs in RJAG containing 1% scaffolds (low stiffness) significantly increased early endothelial and smooth muscle but not cardiac gene expression while in 2% scaffolds (high stiffness) significantly increased only cardiac and not endothelial or smooth muscle gene expression (p<0.05, n≥4). Conclusions: Taken together, these data show that i) Notch1 activation in 3D is dependent on ligand density and scaffold stiffness and ii) stiffness dependent Notch1 activation differentially regulates cardiogenic gene expression in CPCs. Therefore, delivery of CPCs in JAG containing scaffolds could be used to improve cardiac function following MI.

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