It has been found that up-regulation of histone deacetylases 1 (HDAC1) is involved in the development of pulmonary arterial hypertension (PAH). However, it is still unclear whether inhibition of HDAC1 suppresses the development of PAH via restoring miR-34a level in monocrotaline (MCT)-induced PAH rats. PAH rat models were induced by intraperitoneal injection of MCT. HDAC1 was suppressed by intraperitoneal injection of the class I HDAC inhibitor MS-275, and miR-34a was over-expressed via tail vein injection of miR-34a agomiR. HDAC1 protein was significantly increased in MCT-induced PAH rats; this was accompanied with down-regulation of miR-34a and subsequent up-regulation of matrix metalloproteinase 9 (MMP-9)/tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-2/TIMP-2. Administration of PAH rats with MS-275 or miR-34a agomiR dramatically abolished MCT-induced reduction of miR-34a and subsequent up-regulation of MMP-9/TIMP-1 and MMP-2/TIMP-2, finally reduced extracellular matrix (ECM) accumulation, pulmonary arterial remodeling, right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RVHI) in PAH rats. HDAC1 contributes to the development of MCT-induced rat PAH by suppressing miR-34a level and subsequently up-regulating the ratio of MMP-9/TIMP-1 and MMP-2/TIMP-2. Inhibition of HDAC1 alleviates pulmonary arterial remodeling and PAH through up-regulation of miR-34a level and subsequent reduction of MMP-9/TIMP-1 and MMP-2/TIMP-2, suggesting that inhibition of HDAC1 might have potential value in the management of PAH.

中文翻译：

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抑制 HDAC1 通过上调 miR-34a 减轻野百合碱诱导的肺动脉重塑

已发现组蛋白脱乙酰酶 1 (HDAC1) 的上调与肺动脉高压 (PAH) 的发展有关。然而，尚不清楚抑制 HDAC1 是否通过恢复野百合碱 (MCT) 诱导的 PAH 大鼠的 miR-34a 水平来抑制 PAH 的发展。腹腔注射MCT诱导PAH大鼠模型。通过腹腔注射 I 类 HDAC 抑制剂 MS-275 抑制 HDAC1，通过尾静脉注射 miR-34a agomiR 过度表达 miR-34a。HDAC1 蛋白在 MCT 诱导的 PAH 大鼠中显着增加；这伴随着 miR-34a 的下调和随后的基质金属蛋白酶 9 (MMP-9)/金属蛋白酶 1 组织抑制剂 (TIMP-1) 和 MMP-2/TIMP-2 的上调。给予 PAH 大鼠 MS-275 或 miR-34a agomiR 显着消除了 MCT 诱导的 miR-34a 减少和随后 MMP-9/TIMP-1 和 MMP-2/TIMP-2 的上调，最终减少了细胞外基质。 PAH 大鼠的 ECM) 蓄积、肺动脉重塑、右心室收缩压 (RVSP) 和右心室肥大指数 (RVHI)。HDAC1 通过抑制 miR-34a 水平并随后上调 MMP-9/TIMP-1 和 MMP-2/TIMP-2 的比率来促进 MCT 诱导的大鼠 PAH 的发展。抑制 HDAC1 通过上调 miR-34a 水平和随后降低 MMP-9/TIMP-1 和 MMP-2/TIMP-2 来减轻肺动脉重塑和 PAH，表明抑制 HDAC1 可能在管理中具有潜在价值多环芳烃。