Cardiac fibroblasts are pivotal regulators of cardiac homeostasis and are essential in the repair of the heart after myocardial infarction (MI), but their function can also become dysregulated, leading to adverse cardiac remodelling involving both fibrosis and hypertrophy. MicroRNAs (miRNAs) are noncoding RNAs that target mRNAs to prevent their translation, with specific miRNAs showing differential expression and regulation in cardiovascular disease. Here, we show that miR-214–3p is enriched in the fibroblast fraction of the murine heart, and its levels are increased with cardiac remodelling associated with heart failure, or in the acute phase after experimental MI. Tandem mass tagging proteomics and in-silico network analyses were used to explore protein targets regulated by miR-214–3p in cultured human cardiac fibroblasts from multiple donors. Overexpression of miR-214–3p by miRNA mimics resulted in decreased expression and activity of the Piezo1 mechanosensitive cation channel, increased expression of the entire lysyl oxidase (LOX) family of collagen cross-linking enzymes, and decreased expression of an array of mitochondrial proteins, including mitofusin-2 (MFN2), resulting in mitochondrial dysfunction, as measured by citrate synthase and Seahorse mitochondrial respiration assays. Collectively, our data suggest that miR-214–3p is an important regulator of cardiac fibroblast phenotypes and functions key to cardiac remodelling, and that this miRNA represents a potential therapeutic target in cardiovascular disease.

中文翻译：

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MiR-214–3p 调节人心脏成纤维细胞中的 Piezo1、赖氨酰氧化酶和线粒体功能


心脏成纤维细胞是心脏稳态的关键调节者，对于心肌梗死（MI）后心脏的修复至关重要，但它们的功能也可能失调，导致包括纤维化和肥大在内的不良心脏重塑。 MicroRNA (miRNA) 是非编码 RNA，其靶向 mRNA 以阻止其翻译，特定 miRNA 在心血管疾病中表现出差异表达和调节。在这里，我们发现 miR-214–3p 在小鼠心脏的成纤维细胞部分富集，并且其水平随着与心力衰竭相关的心脏重塑或在实验性 MI 后的急性期而增加。使用串联质量标记蛋白质组学和计算机网络分析来探索来自多个供体的培养的人心脏成纤维细胞中 miR-214–3p 调节的蛋白质靶点。 miRNA 模拟物过度表达 miR-214–3p 导致 Piezo1 机械敏感阳离子通道的表达和活性降低，胶原交联酶的整个赖氨酰氧化酶 (LOX) 家族的表达增加，并减少一系列线粒体蛋白的表达，包括 mitofusin-2 (MFN2)，导致线粒体功能障碍，通过柠檬酸合酶和 Seahorse 线粒体呼吸测定进行测量。总的来说，我们的数据表明 miR-214–3p 是心脏成纤维细胞表型和心脏重塑关键功能的重要调节因子，并且该 miRNA 代表了心血管疾病的潜在治疗靶点。