Doxycycline Attenuates Atrial Remodeling by Interfering with MicroRNA-21 and Downstream Phosphatase and Tensin Homolog (PTEN)/Phosphoinositide 3-Kinase (PI3K) Signaling Pathway

Abstract

BackgroundAtrial remodeling especially in the form of fibrosis is the most important substrate of atrial fibrillation (AF). The aim of this study was to investigate the effects of doxycycline on chronic intermittent hypoxia (CIH)-induced atrial remodeling and the pathophysiological mechanisms underlying such changes.Material/MethodsA total of 30 Sprague-Dawley rats were randomized into 3 groups: Control group, CIH group, and CIH with doxycycline treatment group. CIH rats were subjected to CIH 6 h/d for 30 days and treatment rats were administrated doxycycline while they received CIH. After the echocardiography examination, rats were sacrificed at 31 days. The tissues of atria were collected for histological and molecular biological experiments, Masson staining was used to evaluate the extent of atrial fibrosis, microRNA-21, and its downstream target phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K) were assessed.ResultsCompared to the control group, the CIH rats showed higher atrial interstitial collagen fraction, increased microRNA-21, PI3K levels, and decreased PTEN levels. Doxycycline treatment attenuated CIH-induced atrial fibrosis, reduced microRNA-21 and PI3K, and increased PTEN.ConclusionsCIH induced significant atrial remodeling, which was attenuated by doxycycline in our rat model. These changes may be explained due to alterations in the microRNA-21-related signaling pathways by doxycycline.

<p>The Potential Effects of Aliskiren on Atrial Remodeling Induced by Chronic Intermittent Hypoxia in Rats</p>

“…Animal experiments showed that CIH was an important mediator of enhanced atrial vulnerability and susceptibility to AF. 19 Goudis and Ketikoglou 20 described that obstructive sleep apnea was associated with AF, which may implicate the pathophysiological mechanisms of AF. In addition, Zhang et al 21 showed that the percentage of the atrial collagen fraction in the CIH group was significantly increased compared with the values recorded in the control and intervention groups.…”

Genetics and Epigenetics of Atrial Fibrillation

“…Apart from electrical and structural remodeling associated to AF, other miRNAs are involved in AF targeting related pathways, i.e., miR-21 modulates Phosphatase and Tensin Homolog ( PTEN )/Phosphoinositide 3-kinase ( PI3K ) signaling pathway, signal transducer of transcription 3 ( STAT3 ) and Smad7 promoting atrial fibrosis; miR-31 begets arrhythmia by depleting dystrophin and neuronal nitric oxide synthase ( nNOS ); miR-34a is upregulated in AF patients having an important role in the early electrophysiological changes and development of AF via regulation of the expression of Ankyrin-B ( ANK 2 ); and finally, miR-199a down-regulation induces Sirtuin 1 ( SIRT-1 ), a cardio-protective protein, as a compensatory mechanism to inhibit the process of oxidative stress which contributes to the pathogenesis of AF [ 171 , 172 , 173 , 174 , 175 , 176 ].…”

Beneficial effects of tolvaptan on atrial remodeling induced by chronic intermittent hypoxia in rats

“…We then went on to explore the molecular mechanisms underlying such changes. Since miR‐21 plays a crucial role in cardiac fibrosis by affecting ERK and PI3K pathway, we tested the hypothesis that tolvaptan may similarly act via miR‐21/ERK and miR‐21/PI3K pathways for attenuating atrial remodeling. Indeed, our results indicated that CIH induced higher expression levels of miR‐21 and activation of ERK pathway, whereas PI3K/AKT pathway was inhibited in CIH rats.…”