蛋白酶体抑制剂Bortezomib对肺动脉平滑肌细胞钙离子通路的作用研究

Pulmonary hypertension (PH) is a life-threatening disease which included a series of diseases. The increasement of intracellular concentration of Ca2+ of pulmonary artery smooth muscle cells (PASMCs) is the core step in the development of pulmonary artery remodeling which contributes to pulmonary hypertension. Proteasome inhibitor Bortezomib can alleviated pulmonary artery pressure and remodeling in hypoxia and monocrotaline innduced pulmonary hypertension rat model. It is still not known Whether Bortezomib functions by regulating calcium channel. We want to explore effects of Bortezomib on calcium ion channel of pulmonary artery smooth muscle cells in hypoxia induced pulmonary hypertension model. Under hypoxia condition, PPARγ-TRPC1，6 is involved in the increase of Store Operated Calcium Entry(SOCE) which cause the increase of intracellular concentration of Ca2+ of PASMCs. SIMI and ORAI are also involved in SOCE. Thus, we will evaluate effects of Bortezomib on SOCE and PPARγ-TRPC1，6 、SIMI and ORAI in PASMCs in PH model.

肺动脉高压是严重威胁人类健康的一大类疾病，肺动脉平滑肌细胞内钙离子浓度增高进而导致肺动脉重塑是肺动脉高压发病机制的核心环节。蛋白酶体抑制剂Bortezomib可以降低多种肺动脉高压动物模型的肺动脉的压力，减轻肺动脉重塑，然而Bortezomib是否通过钙离子这个环节发挥作用仍不清楚，我们拟通过低氧性肺动脉高压大鼠模型，探讨蛋白酶体抑制剂对肺动脉平滑肌钙离子通道的影响以及与平滑肌细胞增殖迁移的关系。低氧时通过PPARγ-TRPC1，6信号通路使钙池操控性钙内流（SOCE）增加，进而可以导致肺动脉平滑肌细胞内钙离子浓度增加，STIMI和ORAI也是参与SOCE的重要组成部分。我们拟探讨Bortezomib对SOCE的作用以及机制。

肺动脉高压是严重威胁人类健康的一大类疾病，肺动脉平滑肌细胞内钙离子浓度增高进而导致肺动脉重塑是肺动脉高压发病机制的核心环节。蛋白酶体抑制剂Bortezomib可以降低多种肺动脉高压动物模型的肺动脉的压力，减轻肺动脉重塑，然而Bortezomib是否通过钙离子这个环节发挥作用仍不清楚，我们通过低氧性肺动脉高压大鼠模型，探讨蛋白酶体抑制剂对肺动脉平滑肌钙离子通道的影响以及与平滑肌细胞增殖迁移的关系。研究发现，在低氧和野百合碱诱导的两种肺动脉高压动物模型中，硼替佐米（Bortezomib）能够显著降低肺动脉高压的进展。硼替佐米可以显著下降低氧引起的低氧诱导因子（ hypoxia-upregulated HIF-1α）, 骨形成蛋白4（BMP4）, 瞬时受体电位阳离子通道（缺氧TRPC1 and TRPC6）增高。 在肺动脉平滑肌细胞，它可以抑制低氧引起的肺动脉细胞增殖，基础钙水平，及储备操控性钙内流。在大鼠肺动脉平滑肌体内实验及分离培养的平滑肌细胞体外实验，低氧可以使 PPARγ 增高，硼替佐米可以降低低氧引起的 PPARγ 的高表达。硼替佐米也可以明显抑制低氧引起的大鼠肺动脉细胞的ORAI-1的表达。除动物之外，在人的肺动脉平滑肌细胞，蛋白酶体抑制剂对相关蛋白的表达TRPC等也有影响。