P300/CBP-Associated Factor Activates Cardiac Fibroblasts by SMAD2 Acetylation.

Yongwoon Lim,Anna Jeong,Woo-Jin Park,Yeong-Un Lee,Young-Kook Kim,Youngkeun Ahn,Taewon Kook,Duk-Hwa Kwon,Hyun Kook

doi:10.3390/ijms22189944

Abstract

Various heart diseases cause cardiac remodeling, which in turn leads to ineffective contraction. Although it is an adaptive response to injury, cardiac fibrosis contributes to this remodeling, for which the reactivation of quiescent myofibroblasts is a key feature. In the present study, we investigated the role of the p300/CBP-associated factor (PCAF), a histone acetyltransferase, in the activation of cardiac fibroblasts. An intraperitoneal (i.p.) injection of a high dose (160 mg/kg) of isoproterenol (ISP) induced cardiac fibrosis and reduced the amount of the PCAF in cardiac fibroblasts in the mouse heart. However, the PCAF activity was significantly increased in cardiac fibroblasts, but not in cardiomyocytes, obtained from ISP-administered mice. An in vitro study using human cardiac fibroblast cells recapitulated the in vivo results; an treatment with transforming growth factor-β1 (TGF-β1) reduced the PCAF, whereas it activated the PCAF in the fibroblasts. PCAF siRNA attenuated the TGF-β1-induced increase in and translocation of fibrosis marker proteins. PCAF siRNA blocked TGF-β1-mediated gel contraction and cell migration. The PCAF directly interacted with and acetylated mothers against decapentaplegic homolog 2 (SMAD2). PCAF siRNA prevented TGF-β1-induced phosphorylation and the nuclear localization of SMAD2. These results suggest that the increase in PCAF activity during cardiac fibrosis may participate in SMAD2 acetylation and thereby in its activation.

Highlights

IntroductionHeart diseases are the leading cause of morbidity and mortality worldwide and account for nearly a third of deaths in resource-rich countries
We previously reported that histone deacetylase 2 (HDAC2)
We demonstrated that p300/CBP-associated factor (PCAF) acetylates lysine 75 on HDAC2 and thereby increases its deacetylase activity, which otherwise remains suppressed by histone deacetylase 5 (HDAC5) [24]

Summary

Introduction

Heart diseases are the leading cause of morbidity and mortality worldwide and account for nearly a third of deaths in resource-rich countries. Heart failure is a clinical syndrome defined as the inability of the heart to adequately meet the demands of the body for blood and oxygen. It is considered as the final path of various heart diseases. The progression of cardiac remodeling is closely related to structural and functional impairment in the heart under diverse conditions, such as hemodynamic stresses or cardiac injury

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Conclusion