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.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Atrial fibrillation (AF), the most common clinical arrhythmia worldwide, has been well characterized, and it is associated with serious cardiovascular diseases and an increased risk of stroke and death
To investigate whether ubiquitin C-terminal hydrolase 1 (UCHL1) activity is involved in regulating AF, we first tested the expression of UCHL1 in atrial tissues
The mRNA and protein levels of UCHL1 were significantly upregulated in angiotensin II (Ang II)-infused atrial tissues after 3 weeks of infusion (2000 ng/kg/min) compared with saline-infused tissues (Fig. 1a, b)
Summary
Atrial fibrillation (AF), the most common clinical arrhythmia worldwide, has been well characterized, and it is associated with serious cardiovascular diseases and an increased risk of stroke and death. The pathophysiological mechanism of AF is not fully understood, atrial electrical and structural remodeling are the main factors of the persistence and progression of AF [1, 2]. Atrial fibrosis is the hallmark of atrial structural remodeling, which is a common feature of clinical AF [3]. The activation of AT1R stimulates several downstream mediators, including AKT/ERK, TGF-β/Smad, MAP kinases, NADPH oxidase, NF-kB, and hypoxia inducible factor-1alpha (HIF-1α), which are involved in vasoconstriction, fibrosis, inflammation, oxidative stress, and ion channel abnormalities [1, 5,6,7], Ang II-mediated inflammation and oxidative stress are thought to promote atrial fibrosis in AF [2, 8, 9]. The inhibition of the AT1R-mediated activation of signaling is critical for blocking AF development
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