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Inhibition of UCHL1 by LDN-57444 attenuates Ang II–Induced atrial fibrillation in mice
- Source :
- Hypertension Research
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- Atrial fibrillation (AF) is the most common human arrhythmia in clinical practice and may be promoted by atrial inflammation and fibrosis. Ubiquitination is an important posttranslational modification process that is reversed by deubiquitinating enzymes (DUBs). DUBs play critical roles in modulating the degradation, activity, trafficking, and recycling of substrates. However, less research has focused on the role of DUBs in AF. Here, we investigated the effect of ubiquitin C-terminal hydrolase 1 (UCHL1), an important DUB, on the development of AF induced by angiotensin II (Ang II). Male wild-type mice were treated with the UCHL1 inhibitor LDN57444 (LDN) at a dose of 40 μg/kg and infused with Ang II (2000 ng/kg/min) for 3 weeks. Our results showed that Ang II-infused wild-type (WT) mice had higher systolic blood pressure and an increased incidence and duration of AF. Conversely, this effect was attenuated in LDN-treated mice. Moreover, the administration of LDN significantly reduced Ang II-induced left atrial dilation, fibrosis, inflammatory cell infiltration, and reactive oxygen species (ROS) production. Mechanistically, LDN treatment inhibited the activation of multiple signaling pathways (the AKT, ERK1/2, HIF-1α, and TGF-β/smad2/3 pathways) and the expression of CX43 protein in atrial tissues compared with that in vehicle-treated control mice. Overall, our study identified UCHL1 as a novel regulator that contributes to Ang II-induced AF and suggests that the administration of LDN may represent a potential therapeutic approach for treating hypertensive AF.
- Subjects :
- Male
Indoles
Physiology
Blood Pressure
Inflammation
030204 cardiovascular system & hematology
Pharmacology
UCHL1
Article
Deubiquitinating enzyme
Mice
03 medical and health sciences
0302 clinical medicine
Ubiquitin
Fibrosis
Oximes
Internal Medicine
medicine
Animals
Heart Atria
Protein kinase B
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Reactive oxygen species
biology
business.industry
Angiotensin II
medicine.disease
Atrial fibrillation
Deubiquitinase
chemistry
biology.protein
medicine.symptom
Signal transduction
Reactive Oxygen Species
Cardiology and Cardiovascular Medicine
business
Ubiquitin Thiolesterase
Signal Transduction
Subjects
Details
- ISSN :
- 13484214 and 09169636
- Volume :
- 43
- Database :
- OpenAIRE
- Journal :
- Hypertension Research
- Accession number :
- edsair.doi.dedup.....0db3a2f0a07ba81533515cdfab6d2c7f