Sodium butyrate alleviates right ventricular hypertrophy in pulmonary arterial hypertension by inhibiting H19 and affecting the activation of let-7g-5p/IGF1 receptor/ERK
Sodium butyrate alleviates right ventricular hypertrophy in pulmonary arterial hypertension by inhibiting H19 and affecting the activation of let-7g-5p/IGF1 receptor/ERK
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DOI：
10.1016/j.ejphar.2024.176315
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发表时间：
2024-01-05
影响因子：
5
通讯作者：
Zhu，Tian-tian
中科院分区：
文献类型：
--
作者：
Li，Ming-hui;Liu，Xu;Zhu，Tian-tian
肺动脉高压(PAH)是一种复杂而致命的心肺血管疾病。心肌细胞肥大引起的失代偿性右室肥厚(RVH)常导致致死性心力衰竭，是导致患者死亡的主要原因。丁酸钠(SB)是一种已知的抗心肌肥厚的化合物，研究了其潜在的作用及其对PAH-RVH的潜在机制。活体研究表明，SB可减轻MCT-PAH大鼠的RVH和心功能不全，延长寿命和存活率。活体实验表明SB可通过逆转H19、LET-7G-5p、胰岛素样生长因子1受体(IGF1受体)和pERK的表达而减轻心肌肥大。抑制H19可恢复肥大心肌细胞LET-7G-5p的表达，抑制IGF1受体和pERK的过度表达。此外，双荧光素酶分析表明，H19与let-7g-5p有明显的结合，是其内源RNA。总之，SB通过抑制H19的过度表达，恢复LET-7G-5P的水平，并抑制IGF1受体/ERK的激活，从而减轻PAH-RVH。
Pulmonary arterial hypertension (PAH) is a complex and fatal cardio-pulmonary vascular disease. Decompensated right ventricular hypertrophy (RVH) caused by cardiomyocyte hypertrophy often leads to fatal heart failure, the leading cause of mortality among patients. Sodium butyrate (SB), a compound known to reduce cardiac hypertrophy, was examined for its potential effect and the underlying mechanism of SB on PAH-RVH. Thein vivostudy showed that SB alleviated RVH and cardiac dysfunction, as well as improved life span and survival rate in MCT-PAH rats. Thein vivoandin vitroexperiments showed that SB could attenuate cardiomyocyte hypertrophy by reversing the expressions of H19, let-7g-5p, insulin-like growth factor 1 receptor (IGF1 receptor), andpERK. H19 inhibition restored the level of let-7g-5p and prevented the overexpression of IGF1 receptor andpERK in hypertrophic cardiomyocytes. In addition, dual luciferase assay revealed that H19 demonstrated significant binding with let-7g-5p, acting as its endogenous RNA. Briefly, SB attenuated PAH-RVH by inhibiting the H19 overexpression, restoring the level of let-7g-5p, and hindering IGF1 receptor/ERK activation.