HDAC6 Promotes Cardiac Fibrosis Progression through Suppressing RASSF1A Expression.

Abstract

OBJECTIVES:

Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. HDAC6 is a transcriptional regulator of the histone deacetylase family, subfamily 2. Previous studies have shown that HDAC6 plays critical roles in transcription regulation and proliferation events. However, the precise mechanisms of how HDAC is associated with cardiac fibrosis progression have not yet been elucidated.

METHODS:

Fifty adult male Sprague-Dawley (SD) rats were randomly divided into two groups. Cardiac fibrosis was produced by common isoprenaline and cardiac fibroblasts were harvested from SD neonate rats and cultured. The expression of HDAC6, RASSF1A, α-SMA and collagen I were measured by Western blotting and qRT-PCR. Small interfering (si)RNA of HDAC6 affects the proliferation of cardiac fibroblasts and the regulation of RASSF1A/ERK1/2 signaling pathways.

RESULTS:

In this study, we found that mRNA and protein levels of HDAC6 were upregulated in cardiac fibrosis tissues and activated cardiac fibroblast cells. Inhibition of HDAC6 by siRNA or the inhibitor tubacin attenuated the TGF-β1-induced myofibroblast markers. In contrast, HDAC6 knockdown using siRNA inhibited cardiac fibroblast cell proliferation. Furthermore, we demonstrated that knockdown of HDAC6 elevated RASSF1A expression in activated cardiac fibroblasts, and treatment of cardiac fibroblasts with the HDAC6 inhibitor tubacin also elevated RASSF1A expression.

CONCLUSIONS:

The results of this study suggest that a previously unknown mechanism of HDAC6 inactivation of RASSF1A controls cardiac fibroblast proliferation and fibrosis.

• Authors: Hui Tao, Jing-Jing Yang, Wei Hu, Kai-Hu Shi, Jun Li
• Journal: Cardiology (Cardiology) Vol. 133 Issue 1 Pg. 18-26 ( 2016) ISSN: 1421-9751 [Electronic] Switzerland
• PMID: 26401643 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 S. Karger AG, Basel.

Chemical References

• Actins
• Anilides
• Collagen Type I
• Collagen Type I, alpha 1 Chain
• Hydroxamic Acids
• RASSF1 protein, rat
• RNA, Small Interfering
• Transforming Growth Factor beta1
• Tumor Suppressor Proteins
• smooth muscle actin, rat
• tubacin
• HDAC6 protein, rat
• Histone Deacetylase 6
• Histone Deacetylases
• Isoproterenol

Topics

• Actins (metabolism)
• Anilides (pharmacology)
• Animals
• Cell Proliferation
• Cells, Cultured
• Collagen Type I (metabolism)
• Collagen Type I, alpha 1 Chain
• Disease Models, Animal
• Fibrosis
• Histone Deacetylase 6
• Histone Deacetylases (genetics, metabolism)
• Hydroxamic Acids (pharmacology)
• Isoproterenol
• Male
• Myocardium (pathology)
• Myofibroblasts (metabolism)
• RNA, Small Interfering
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (genetics)
• Transforming Growth Factor beta1 (pharmacology)
• Tumor Suppressor Proteins (genetics, metabolism)