MALAT1/miR-503相关自噬途径与低氧性肺血管重建关系的分子机制和双氢青蒿素的干预研究

Pulmonary hypertension can be manifested as pulmonary vascular structural remodeling and vascular homeostasis. There is a growing interest in relationship between autophagy and pulmonary hypertension. Our previous research has indicated that the proliferation of pulmonary artery smooth muscle cells (PASMC) could be promoted and autophagy could compensatively increase under hypoxia. Simultaneously, our data demonstrated that inhabitation of PI3K/AKT/mTOR signal pathway can promote autophagic death of PASMC. In study of pulmonary fibrosis, the expression of lncRNA MALAT1 and miR-503 changes in pulmonary hypertension. Moreover, the MALAT1 was reported as a ceRNA to competitively decrease the expression of miR-503, and miR-503 may inhibit the expression of PI3K. Based on studies above mentioned and data of our previous research ,we speculate that MALAT1/miR-503 may regulate PI3K-mediated autophagy pathway. Aiming to find a new target of pulmonary hypertension treatment, this project intends to explore the relationship between MALAT1/miR-503 related autophagy pathway and pulmonary hypertension caused by hypoxia. In addition, our prophase study has found that dihydroartemisinin (DHA) could decrease hypoxic-induced pulmonary hypertension in rats and activate autophagy. Under hypoxia, DHA can inhibit the expression of MALAT1 in lung tissue. Besides,it has been reported that DHA can inhibit the expression of PI3K in glioma cells . Therefore, this project aims to further investigate the role of DHA on PI3K-mediated autophagy pathway in PASMC, and to confirm the function of MALAT1/miR-503 in this pathophysiological process. This study will be helpful in providing more explicit evidence to support its widespread use of prevention and treatment of pulmonary hypertension.

肺血管结构重建和血管稳态失衡是肺动脉高压的主要特征，自噬与其关系近来备受关注。本团队前期研究发现，低氧使肺动脉平滑肌细胞（PASMC）增殖、自噬代偿性升高，抑制PI3K/AKT/mTOR可促进PASMC自噬性死亡。据报道lncRNA MALAT1、miR-503表达在肺动脉高压时出现变化，MALAT1作为ceRNA可下调miR-503表达，miR-503可抑制PI3K表达，故推测MALAT1/miR-503调控PI3K介导的自噬途径。故本项目拟研究MALAT1/miR-503相关自噬途径与低氧性肺动脉高压的关系，为其诊治寻求新靶点。本团队还发现双氢青蒿素（DHA）可抑制低氧性肺动脉高压并促进自噬，且抑制MALAT1表达。有报道DHA可抑制胶质瘤细胞PI3K表达，故本项目进一步探讨DHA对PI3K介导的PASMC自噬的影响以及MALAT1/miR-503的调控作用，为其临床应用提供实验依据。

低氧肺动脉高压是一种慢性疾病，目前认为肺血管结构重建是肺动脉高压持续发展和对血管扩张药产生抵抗的主要原因。因此探明导致肺动脉高压肺血管重建的分子机制和有效靶点，为其寻找新的药物和治疗途径以延缓肺动脉高压进展成为十分重要的研究课题。本课题组前期研究发现，PI3K/AKT/mTOR自噬通路与低氧肺动脉高压关系密切。LncRNA MALAT1/miR-503作为其上游通路，参与了肺动脉高压的发生发展。而本课题组前期研究发现，双氢青蒿素可降低低氧诱导的大鼠肺动脉高压，且促进自噬相关蛋白表达并抑制MALAT1的表达。故本项目在整体、细胞和分子水平，首先发现双氢青蒿素可缓解低氧下大鼠以及小鼠的肺动脉高压、肺血管重建以及右心室肥厚，且双氢青蒿素可通过抑制mTOR从而促进低氧下自噬水平。其次，本项目进一步发现miR-503可通过抑制PI3K/AKT通路减轻低氧大鼠肺动脉平滑肌细胞增殖和迁移，而双氢青蒿素通过上调miR-503进而抑制 PI3K/AKT 通路减轻低氧诱导的肺动脉平滑肌细胞增殖和迁移。最后，本项目证实MALAT1可促进低氧下肺动脉平滑肌细胞增殖以及迁移，而双氢青蒿素可通过下调MALAT1从而减轻低氧诱导的肺动脉平滑肌细胞增殖和迁移。本项目达到了预期的研究目的，这项成果对于低氧肺动脉高压的机制研究具有重要的意义，同时也为双氢青蒿素在低氧肺动脉高压患者上的临床推广应用提供了更确切的实验研究依据。