Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
Life Sci. 2023 Jan 1;312:121192. doi: 10.1016/j.lfs.2022.121192. Epub 2022 Nov 14.
SIRT6 is an NAD-dependent protein that plays a vital role in regulating the cell proliferation, differentiation and apoptosis. Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) in peripheral vascular is one of the major pathological findings of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). However, whether SIRT6 is involved in hypoxia-induced proliferation of PASMCs and its possible mechanisms remain unknown. In the present study, we found that the expression of SIRT6 was decreased in both hypoxia-induced PAH rats model and HPASMCs. Hypoxia promoted the proliferation of HPASMCs in a time-dependent manner, inhibited the activity of caspase-3 and the production of PDH, increased the activity of LDH, ROS level, mitochondrial membrane potential(MMP) and the expression of HIF-1α and PDK4, which induced glycolysis. SIRT6 over-expression could inhibit the proliferation of HPASMCs and increase the apoptosis rate, impelled the retardation of cell cycle in phase G1. Meanwhile, SIRT6 over-expression reduced LDH activity, the levels of ROS and MMP, which simultaneously increased the production of PDH, the expression of HIF-1α, PDK4, Cyclin D1 and PCNA in hypoxia-induced HPASMCs. Moreover, SIRT6 over-expression inhibited the transcriptional activation of HIF-1α/PDK4 signaling. In addition, SIRT6 knockdown with SIRT6 siRNA exhibited the same effect as hypoxia. Together, our results indicated that SIRT6 was participant in regulating hypoxia-induced imbalance of proliferation and apoptosis of HPASMCs, which was associated with the activation of HIF-1α/PDK4 signaling pathway. Targeting at SIRT6 gene and regulating the downstream metabolism signaling pathway may be a novel strategy for the treatment of hypoxia-induced PAH.
SIRT6 是一种 NAD 依赖性蛋白，在调节细胞增殖、分化和凋亡方面起着至关重要的作用。外周血管中肺动脉平滑肌细胞（PASMCs）的异常增殖是肺动脉高压（PAH）肺血管重构的主要病理发现之一。然而，SIRT6 是否参与缺氧诱导的 PASMC 增殖及其可能的机制尚不清楚。在本研究中，我们发现 SIRT6 的表达在缺氧诱导的 PAH 大鼠模型和 HPASMCs 中均降低。缺氧以时间依赖性方式促进 HPASMCs 的增殖，抑制 caspase-3 的活性和 PDH 的产生，增加 LDH 的活性、ROS 水平、线粒体膜电位（MMP）和 HIF-1α 和 PDK4 的表达，从而诱导糖酵解。SIRT6 的过表达可抑制 HPASMCs 的增殖并增加细胞凋亡率，促使细胞周期在 G1 期停滞。同时，SIRT6 的过表达降低了 LDH 活性、ROS 和 MMP 的水平，同时增加了 PDH 的产生、HIF-1α、PDK4、Cyclin D1 和 PCNA 在缺氧诱导的 HPASMCs 中的表达。此外，SIRT6 的过表达抑制了 HIF-1α/PDK4 信号的转录激活。此外，用 SIRT6 siRNA 敲低 SIRT6 表现出与缺氧相同的效果。总之，我们的研究结果表明，SIRT6 参与调节缺氧诱导的 HPASMCs 增殖和凋亡失衡，这与 HIF-1α/PDK4 信号通路的激活有关。针对 SIRT6 基因并调节下游代谢信号通路可能是治疗缺氧诱导的 PAH 的一种新策略。
