Abstract
BackgroundIt 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.MethodsPAH 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.ResultsHDAC1 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.ConclusionsHDAC1 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.
Highlights
It has been found that up-regulation of histone deacetylases 1 (HDAC1) is involved in the development of pulmonary arterial hypertension (PAH)
After 28 days of MCT injection, the right ventricular systolic pressure (RVSP) in MCT-treated rats was significantly increased compared with the control group (56.45 ± 2.54 mmHg versus 21.70 ± 1.70 mmHg, P < 0.05), suggesting that PAH was successfully induced by MCT in rats
After administration of MS-275 in rats exposed to MCT, the right ventricle (RV)/(LV + S) ratio was declined to 0.35 ± 0.04 (P < 0.05 versus MCT group)
Summary
It has been found that up-regulation of histone deacetylases 1 (HDAC1) is involved in the development of pulmonary arterial hypertension (PAH). It is still unclear whether inhibition of HDAC1 suppresses the development of PAH via restoring miR-34a level in monocrotaline (MCT)-induced PAH rats. Histone acetylation is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), playing an important role in controlling gene expression [5]. Class I HDACs (HDAC1, 2, 3, and 8) play an important role in controlling cell cycle regulation, ECM accumulation and tissue development by deacetylating substrates and regulating gene expression [7,8,9]. Studies have shown that the overall activity of HDACs is determined by the expression level of HDAC1 to some extent [10]
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