Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210008, China.
Biomed Res Int. 2022 Oct 4;2022:9294148. doi: 10.1155/2022/9294148. eCollection 2022.
Right ventricular (RV) failure determines the prognosis in pulmonary arterial hypertension (PAH), but the underlying mechanism is still unclear. Growing evidence has shown that microRNAs participate in RV remodeling. This study is undertaken to explore the role of miR-335-5p in regulating RV remodeling induced by PAH. Two PAH models were used in the study, including the monocrotaline rat model and hypoxia/su5416 mouse model. miRNA sequencing and RT-qPCR validation identified that miR-335-5p was elevated in the RV of PAH rats. In vitro, miR-335-5p expression was increased after angiotensin II treatment, and miR-335-5p inhibition relieved angiotensin II-induced cardiomyocyte hypertrophy. The luciferase reporter assay showed that calumenin was a target gene for miR-335-5p. Pretreatment with miR-335-5p inhibitors could rescue calumenin downregulation induced by angiotensin II in H9C2 cells. Moreover, intracellular Ca concentration and apoptosis were increased after angiotensin II treatment, and miR-335-5p inhibition decreased intracellular Ca accumulation and apoptosis. Finally, in vivo miR-335-5p downregulation (antagomir miR-335-5p) attenuated RV remodeling and rescued calumenin downregulation under conditions of hypoxia/su5416 exposure. Our work highlights the role of miR-335-5p and calumenin in RV remodeling and may lead to the development of novel therapeutic strategies for right heart failure.
右心室（RV）衰竭决定了肺动脉高压（PAH）的预后，但潜在机制仍不清楚。越来越多的证据表明 microRNAs 参与 RV 重塑。本研究旨在探讨 miR-335-5p 在调节 PAH 诱导的 RV 重塑中的作用。该研究使用了两种 PAH 模型，包括野百合碱大鼠模型和缺氧/Su5416 小鼠模型。miRNA 测序和 RT-qPCR 验证表明，miR-335-5p 在 PAH 大鼠的 RV 中升高。在体外，血管紧张素 II 处理后 miR-335-5p 的表达增加，而 miR-335-5p 抑制减轻了血管紧张素 II 诱导的心肌细胞肥大。荧光素酶报告基因检测表明钙网蛋白是 miR-335-5p 的靶基因。用 miR-335-5p 抑制剂预处理可以挽救血管紧张素 II 在 H9C2 细胞中引起的钙网蛋白下调。此外，血管紧张素 II 处理后细胞内 Ca 浓度和细胞凋亡增加，而 miR-335-5p 抑制减少了细胞内 Ca 积累和细胞凋亡。最后，体内 miR-335-5p 下调（antagomir miR-335-5p）减轻了缺氧/Su5416 暴露条件下 RV 重塑，并挽救了钙网蛋白下调。我们的工作强调了 miR-335-5p 和钙网蛋白在 RV 重塑中的作用，并可能为右心衰竭的治疗策略的发展提供新的思路。
