Key result
Inhibition of HDAC1 with MS-275 attenuated the effects of angiotensin II in human cardiac fibroblasts by reducing mitochondrial ROS generation and calcium overload.
Why the study?
Inhibition of HDACs attenuates cardiac fibrosis, but whether class I HDAC inhibition attenuates ANG II-induced fibrogenesis and mitochondrial malfunction in human cardiac fibroblasts remained to be evaluated.
Does MS-275 attenuate angiotensin II-induced fibrogenesis and mitochondrial malfunction in human cardiac fibroblasts?
Does MS-275 attenuate angiotensin II-induced fibrogenesis and mitochondrial malfunction in human cardiac fibroblasts?
Modulating mitochondrial function via class I HDAC inhibition may be a novel strategy for controlling cardiac fibroblast activity and attenuating cardiac fibrosis.
MS-275 effects on fibroblast mitochondria remain preclinical; leaves open class I HDAC inhibition as an antifibrotic strategy pending in vivo trials.
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: 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.
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Huynh et al. (2021) studied Cardiac fibrosis. MS-275 (HDAC class 1 inhibitor) vs. Control (without or with ANG II 100 nM) was evaluated on Mitochondrial ROS generation and calcium overload. Inhibition of HDAC1 with MS-275 attenuated the effects of angiotensin II in human cardiac fibroblasts by reducing mitochondrial ROS generation and calcium overload.
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