Class I HDAC modulates angiotensin II–induced fibroblast migration and mitochondrial overactivity

• Published in: European journal of clinical investigation Vol. 52; no. 4; pp. e13712 - n/a
• Main Authors: Huynh, Tin Van, Rethi, Lekha, Chung, Cheng‐Chih, Yeh, Yung‐Hsin, Kao, Yu‐Hsun, Chen, Yi‐Jen
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-04-2022
• Subjects: Adenosine triphosphate; Angiotensin; Angiotensin II; Angiotensin II - drug effects; Angiotensin II - physiology; ATP; Attenuation; Calcium; Calcium (mitochondrial); Calcium - metabolism; Calcium influx; Calcium ions; cardiac fibrosis; Cell Movement - physiology; Cells, Cultured; class I histone deacetylases; Electron transport; Fibroblasts; Fibroblasts - physiology; Fibrosis; Fluorescence; Heart; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - physiology; Histones; Humans; Mitochondria; Mitochondria - drug effects; Mitochondria - physiology; Myocardium - cytology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Respiration; Western blotting; class I histone deacetylases; cardiac fibrosis; angiotensin II; mitochondria; reactive oxygen species
• ISSN: 0014-2972; 1365-2362
• DOI: 10.1111/eci.13712

Background
Inhibition of histone deacetylases (HDACs) attenuates cardiac fibrosis. In this study, we evaluated whether the inhibition of class I HDACs can attenuate angiotensin II (ANG II)–induced fibrogenesis and mitochondrial malfunction through its effects on reactive oxygen species (ROS) and calcium dysregulation in human cardiac fibroblasts (CFs).
Methods
Seahorse XF24 extracellular flux analyser, fluorescence staining, Western blotting, HDAC activity assays and Transwell migration assay were used to study mitochondrial respiration, adenosine triphosphate (ATP) production, mitochondrial calcium uptake and ROS, HDAC expression and activity and fibroblast activity in CFs without (control) or with ANG II (100 nM) and/or MS‐275 (HDAC class 1 inhibitor, 10 μM) for 24 h.
Results
ANG II increased HDAC activity without changing protein expression in CFs. Compared with controls, ANG II‐treated CFs had greater migration activity, higher ATP production, maximal respiration and spare capacity with higher mitochondrial Ca2+ uptake and ROS generation, which was attenuated by the administration of MS‐275. ANG II activated CFs by increasing mitochondrial calcium content and ATP production, which may be caused by increased HDAC activity. Inhibition of HDAC1 attenuated the effects of ANG II by reducing mitochondrial ROS generation and calcium overload.
Conclusions
Modulating mitochondrial function by regulation of HDAC may be a novel strategy for controlling CF activity.