SREBP-1c调控Randle循环--胰岛素抵抗代谢通路在肺动脉高压血管重构中的作用

Pulmonary hypertension (PAH) is closely related to metabolic disorders. IR promotes vascular smooth muscle cell (SMC) proliferation. SMC proliferation is the main pathological change of PAH vascular remodeling. In our previous study, we found that PAH rats had IR, and the IR related metabolic enzymes and glucose-fatty acid cycle (Randle cycle) were significantly changed. The expression of SREBP-1c, an important transcriptional regulator of metabolic enzymes, was decreased in PAH rats. However, the mechanism is not clear. Based on the above study, we hypothesized that SREBP-1c is the core link of metabolic disorder in PAH, which reprogramed metabolic pattern，participated in IR and vascular remodeling by Randle cycle. In this study, the effects of SREBP-1c on vascular remodeling in hypoxia PAH were determined using cell transfection in SREBP-1c-/- SMC and gene knockout in SREBP-1c-/- mice. The level of energy metabolism, IR, SMC proliferation and other indexex in hypoxia SREBP-1c-/- mice and their SMC were analyzed through blocking the Randle cycle and the insulin signal.It may clarify the effect of SREBP-1c on pulmonary vascular remodeling by regulating Randle cycle-IR pathway, and provide a new target for the prevention and treatment of PAH.

肺动脉高压(PAH)与代谢紊乱密切相关。胰岛素抵抗(IR)促进血管平滑肌细胞(SMC)增殖。SMC增殖是PAH血管重构主要病理改变。我们前期研究发现，PAH存在IR，导致IR的多种代谢酶及酶参与的葡萄糖-脂肪酸循环(Randle循环)代谢模式明显变化，调节脂代谢重要的转录调节因子SREBP-1c表达减少，但具体机制尚不清楚。基于上述研究，我们假设：SREBP-1c是PAH代谢障碍的核心环节，它通过Randle循环重编代谢模式介导IR，参与血管重构。本课题拟通过细胞转染及小鼠SREBP-1c基因敲除技术，观察SREBP-1c对低氧性PAH小鼠血管重构的影响；并用工具药分别阻断Randle循环和胰岛素信号，分析能量代谢、IR及细胞增殖等指标，从多个层面阐明SREBP-1c调节Randle循环-IR通路对肺血管重构的影响，为PAH防治提供新靶点。

肺动脉高压(PAH)与代谢紊乱密切相关。我们研究发现，PAH中可观察到葡萄糖-脂肪酸循环(Randle循环)代谢模式发生明显变化以及胰岛素信号通路的缺陷。我们以野百合碱诱导的肺动脉高压大鼠和肺动脉平滑肌细胞为研究对象，发现在PAH中HK-II、P-ACC1/ACC1、P-ACC2/ACC2表达增强，SREBP1-c表达减弱。因此我们可以得出，PAH中糖酵解增强，葡萄糖的有氧氧化被抑制，通过Randle循环进而使得脂肪酸氧化增强。另外，我们还发现，在PAH中PKC磷酸化水平增加，介导IRS1丝氨酸磷酸化水平增加，进而异常激活MAPK通路，促进肺动脉平滑肌细胞的增殖。综上，我们阐明了PAH的发生发展与代谢紊乱、Randle循环以及胰岛素信号通路缺陷的关系，为PAH的防治提供了潜在的治疗靶点。