Pulmonary arterial hypertension (PAH) is the most common form of pulmonary hypertension. Pulmonary arterial remodeling is closely related to the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs), which leads to the thickening of the medial layer of muscular arteries and then results in the narrowing or occlusion of the precapillary arterioles and PAH. However, the mechanisms underlying the abnormal proliferation of PASMCs remain unclear. In this study, we established rat primary PAH models using monocrotaline (MCT) injection or hypoxic exposure, then investigated the expression patterns of seven miRNAs associated with multiple pathogenic pathways central to pulmonary hypertension, and further explored the roles and the possible mechanisms of miR-135a during the development of PAH. In the rat primary PAH models, we observed that the expression of miR-135a-5p in lungs was drastically decreased at the initial stage of PAH development after MCT administration or hypoxic exposure, but it increased by 12-fold or 10-fold at the later stage. In vitro study in PASMCs showed a similar pattern of miR-135a-5p expression, with downregulation at 6 h but upregulation at 18, 24, and 48 h after hypoxic exposure. Early, but not late, administration of a miR-135a-5p mimic inhibited hypoxia-induced proliferation of PASMCs. The protective role of early miR-135a-5p agomir in the PAH rat model further supported the hypothesis that the early decrease in the expression of miR-135a-5p contributes to the proliferation of PASMCs and development of PAH, as early administration of miR-135a-5p agomir (10 nM, i.v.) reversed the elevated mean pulmonary arterial pressure and pulmonary vascular remodeling in MCT-treated rats. We revealed that miR-135a-5p directly bound to the 3'-UTR sequence of rat transient receptor potential channel 1 (TRPC1) mRNA and decreased TRPC1 protein expression, thus inhibiting PASMC proliferation. Collectively, our data suggest that dysregulation of miR-135a-5p in PASMCs contributes to the abnormal proliferation of PASMCs and the pathogenesis of PAH. Increasing miR-135a-5p expression at the early stage of PAH is a potential new avenue to prevent PAH development.

中文翻译：

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miR-135a-5p的失调促进了体内和体外大鼠肺动脉高压的发展。

肺动脉高压（PAH）是最常见的肺动脉高压形式。肺动脉重塑与肺动脉平滑肌细胞（PASMC）的异常增殖密切相关，后者导致肌肉动脉内侧层增厚，进而导致毛细血管前动脉和PAH变窄或闭塞。但是，PASMCs异常增殖的潜在机制仍不清楚。在这项研究中，我们使用单芥子碱（MCT）注射或低氧暴露建立了大鼠原发性PAH模型，然后研究了与肺动脉高压相关的多种致病途径相关的7种miRNA的表达模式，并进一步探讨了miR-的作用和可能的机制PAH开发过程中的135a。在大鼠原发性PAH模型中，我们观察到，在给予MCT或低氧暴露后，PAH发育的最初阶段，miR-135a-5p在肺中的表达急剧下降，但在后期则增加了12倍或10倍。在PASMC中进行的体外研究显示了miR-135a-5p表达的相似模式，在低氧暴露后6小时下调，但在18、24和48小时后上调。早期但不晚于miR-135a-5p模拟物的给药可抑制缺氧诱导的PASMCs增殖。早期miR-135a-5pagomir在PAH大鼠模型中的保护作用进一步支持了以下假设，即miR-135a-5p表达的早期降低有助于PASMC的增殖和PAH的发育。 135a-5p agomir（10 nM，IV ）逆转了接受MCT治疗的大鼠的平均肺动脉压升高和肺血管重构。我们揭示了miR-135a-5p直接与大鼠瞬时受体电位通道1（TRPC1）mRNA的3'-UTR序列结合并降低了TRPC1蛋白的表达，从而抑制了PASMC的增殖。总体而言，我们的数据表明，PASMCs中miR-135a-5p的失调有助于PASMCs的异常增殖和PAH的发病机理。在PAH早期增加miR-135a-5p表达是预防PAH发生的潜在新途径。我们的数据表明，PASMCs中miR-135a-5p的失调有助于PASMCs的异常增殖和PAH的发病机理。在PAH早期增加miR-135a-5p表达是预防PAH发生的潜在新途径。我们的数据表明，PASMCs中miR-135a-5p的失调有助于PASMCs的异常增殖和PAH的发病机理。在PAH早期增加miR-135a-5p表达是预防PAH发生的潜在新途径。