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Cardiac fibroblast‑myofibroblast transformation (FMT) contributes to the fibrotic deterioration evoked by chronic hypoxia. Growing evidence implicates long noncoding RNAs (lncRNAs) in various types of cardiac physiological and pathological processes, especially in cardiac fibrosis. In the present study, the lncRNA Taurine Upregulated Gene 1 (TUG1), reported as a regulator of hypoxia fibrosis in the lungs, was found to also be an important regulator of cardiac FMT. Specifically, the possible role of TUG1 in cardiac FMT and fibrosis under chronic hypoxia was investigated. It was revealed that the degree of fibrosis in heart tissues collected from congenital heart surgery patients with low pulse oxygen saturation and mice housed under chronic hypoxic and atmospheric pressure conditions was negatively correlated with pulse oxygen saturation. Moreover, TUG1 expression was positively correlated with the degree of fibrosis but negatively correlated with pulse oxygen saturation. Cardiac fibroblasts showed increased myofibroblast marker, collagen I and α‑SMA expression levels as the hypoxia time increased. TUG1 knockdown ameliorated the hypoxia‑induced FMT. A bioinformatics analysis predicted that TUG1 had miR‑29c binding sites in its 3'‑UTR and miR‑29c is a key regulator of cardiac fibrosis. The present study demonstrated that TUG1, along with miR‑29c, may contribute to cardiac FMT activation and promote fibrosis in chronic hypoxia.

Atrial fibrillation (AF) has a high prevalence and recurrence rate, and is associated with substantial mortality. However, its underlying mechanisms are not thoroughly understood. Increasing attention has been paid to the roles of microRNAs (miRs) in the pathogenesis of cardiovascular disease, including miR‑1 and miR‑133 (in the electrophysiological response), and miR‑34a (in cardiac fibrosis). Recently, Ankyrin‑B (Ank‑B), an adaptor protein, has been demonstrated to be associated with AF. As a predicted target gene of miR‑34a, the present study aimed to investigate if miR‑34a has a role in AF via regulation of Ank‑B expression. Western blot analysis revealed that the expression levels of Ank‑B was lower in the atrial tissue of AF patients than in individuals with sinus rate (SR); however, reverse transcription‑quantitative polymerase chain reaction data demonstrated that miR‑34a expression exhibited the opposite pattern. Dual‑luciferase assays following the specific overexpression or inhibition of miR‑34a indicated that the 3' untranslated region of Ankyrin 2 (the gene encoding Ank‑B) contained binding sites for miR‑34a. Furthermore, the expression levels of Ank‑B and sodium‑calcium exchanger 1 (an Ank‑B binding partner important in Ca2+ homeostasis), as well as intracellular Ca2+ signaling detected by Fluoro‑3 AM, were altered following the modulation of miR‑34a expression. Thus, miR‑34a may serve an important role in early electrophysiological remodeling and the development of AF via the regulation of Ank‑B expression. These results offer valuable insight into the underlying mechanism of AF, and provide a promising target for developing clinical diagnostic tools and potential therapies for patients with AF.

Cardiomyocytes experience a series of complex endogenous regulatory mechanisms against apoptosis induced by chronic hypoxia. MicroRNAs are a class of endogenous small non-coding RNAs that regulate cellular pathophysiological processes. Recently, microRNA-138 (miR-138) has been found related to hypoxia, and beneficial for cell proliferation. Therefore, we intend to study the role of miR-138 in hypoxic cardiomyocytes and the main mechanism. Myocardial samples of patients with congenital heart disease (CHD) were collected to test miR-138 expression. Agomir or antagomir of miR-138 was transfected into H9C2 cells to investigate its effect on cell apoptosis. Higher miR-138 expression was observed in patients with cyanotic CHD, and its expression gradually increased with prolonged hypoxia time in H9C2 cells. Using MTT and LDH assays, cell growth was significantly greater in the agomir group than in the negative control (NC) group, while antagomir decreased cell survival. Dual luciferase reporter gene and Western-blot results confirmed MLK3 was a direct target of miR-138. It was found that miR-138 attenuated hypoxia-induced apoptosis using TUNEL, Hoechst staining and Annexin V-PE/7-AAD flow cytometry analysis. We further detected expression of apoptosis-related proteins. In the agomir group, the level of pro-apoptotic proteins such as cleaved-caspase-3, cleaved-PARP and Bad significantly reduced, while Bcl-2 and Bcl-2/Bax ratio increased. Opposite changes were observed in the antagomir group. Downstream targets of MLK3, JNK and c-jun, were also suppressed by miR-138. Our study demonstrates that up-regulation of miR-138 plays a protective role in myocardial adaptation to chronic hypoxia, which is mediated mainly by MLK3/JNK/c-jun signaling pathway.