HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling

Author:

Travers Joshua G.12ORCID,Wennersten Sara A.12ORCID,Peña Brisa12ORCID,Bagchi Rushita A.12ORCID,Smith Harrison E.34,Hirsch Rachel A.3,Vanderlinden Lauren A.4,Lin Ying-Hsi12,Dobrinskikh Evgenia5,Demos-Davies Kimberly M.1,Cavasin Maria A.12,Mestroni Luisa1ORCID,Steinkühler Christian6,Lin Charles Y.37,Houser Steven R.8ORCID,Woulfe Kathleen C.1,Lam Maggie P.Y.12ORCID,McKinsey Timothy A.12ORCID

Affiliation:

1. Department of Medicine, Division of Cardiology (J.G.T., S.A.W., B.P., R.A.B., Y.-H.L., K.M.D.-D., M.A.C., L.M., K.C.W., M.P.Y.L., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora.

2. Consortium for Fibrosis Research & Translation (J.G.T., S.A.W., B.P., R.A.B., Y.-H.L., M.A.C., M.P.Y.L., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora.

3. Molecular and Human Genetics, Baylor College of Medicine, Houston, TX (H.E.S., R.A.H., C.Y.L.)

4. Department of Biostatistics and Informatics (H.E.S., L.A.V.), Colorado School of Public Health, Aurora.

5. Department of Medicine, Division of Pulmonary Sciences & Critical Care (E.D.), University of Colorado Anschutz Medical Campus, Aurora.

6. Italfarmaco SpA (C.S.), Cinisello Balsamo, Italy.

7. now with Kronos Bio, Cambridge, MA (C.Y.L.).

8. Cardiovascular Research Center (S.R.H.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA.

Abstract

Background: Diastolic dysfunction (DD) is associated with the development of heart failure and contributes to the pathogenesis of other cardiac maladies, including atrial fibrillation. Inhibition of histone deacetylases (HDACs) has been shown to prevent DD by enhancing myofibril relaxation. We addressed the therapeutic potential of HDAC inhibition in a model of established DD with preserved ejection fraction. Methods: Four weeks after uninephrectomy and implantation with deoxycorticosterone acetate pellets, when DD was clearly evident, 1 cohort of mice was administered the clinical-stage HDAC inhibitor ITF2357/Givinostat. Echocardiography, blood pressure measurements, and end point invasive hemodynamic analyses were performed. Myofibril mechanics and intact cardiomyocyte relaxation were assessed ex vivo. Cardiac fibrosis was evaluated by picrosirius red staining and second harmonic generation microscopy of left ventricle (LV) sections, RNA sequencing of LV mRNA, mass spectrometry–based evaluation of decellularized LV biopsies, and atomic force microscopy determination of LV stiffness. Mechanistic studies were performed with primary rat and human cardiac fibroblasts. Results: HDAC inhibition normalized DD without lowering blood pressure in this model of systemic hypertension. In contrast to previous models, myofibril relaxation was unimpaired in uninephrectomy/deoxycorticosterone acetate mice. Furthermore, cardiac fibrosis was not evident in any mouse cohort on the basis of picrosirius red staining or second harmonic generation microscopy. However, mass spectrometry revealed induction in the expression of >100 extracellular matrix proteins in LVs of uninephrectomy/deoxycorticosterone acetate mice, which correlated with profound tissue stiffening based on atomic force microscopy. ITF2357/Givinostat treatment blocked extracellular matrix expansion and LV stiffening. The HDAC inhibitor was subsequently shown to suppress cardiac fibroblast activation, at least in part, by blunting recruitment of the profibrotic chromatin reader protein BRD4 (bromodomain-containing protein 4) to key gene regulatory elements. Conclusions: These findings demonstrate the potential of HDAC inhibition as a therapeutic intervention to reverse existing DD and establish blockade of extracellular matrix remodeling as a second mechanism by which HDAC inhibitors improve ventricular filling. Our data reveal the existence of pathophysiologically relevant covert or hidden cardiac fibrosis that is below the limit of detection of histochemical stains such as picrosirius red, highlighting the need to evaluate fibrosis of the heart using diverse methodologies.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

Cited by 84 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3