Cao Fangying, Liu Xiaoxiao, Cao Xiangrong, Wang Shaoping, Fu Kun, Zhao Yejing, Shen Fang, Liu Jinghua
Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
Biochem Biophys Res Commun. 2017 Sep 23;491(3):578-586. doi: 10.1016/j.bbrc.2017.07.160. Epub 2017 Jul 31.
Vascular calcification is prevalent and associated with adverse outcome without available therapy. The benefits of fibroblast growth factor (FGF)-21 on metabolism and atherosclerosis make it a promising therapeutic agent for vascular calcification. We investigated the effects of FGF21 on vascular smooth muscle cell (VSMC) calcification by culturing rat VSMCs in a calcifying medium for 9days. FGF21 markedly attenuated mineral deposition and apoptosis at the indicated time points. In the presence of FGF21, the expression levels of osteoblastic protein including bone morphogenic protein-2, alkaline phosphatase(ALP), runt-related transcription factor(RUNX)-2 and nuclear factor-kappa B ligand (RANKL) were down-regulated, whereas the expression of osteoprotegerin (OPG) increased. Knockdown of OPG significantly impaired inhibition of FGF21 on apoptosis and the expression of pro-apoptotic genes including caspase-3 and Bax and osteoblastic -promoting markers including ALP, RUNX-2 and RANKL. Furthermore, FGF21 facilitated the phosphoryl of AKT but suppressed P38, while OPG knockdown attenuated the effects. LY29400 (inhibitor of PI3K) abrogated the activation of PI3K/AKT and SB203580 (inhibitor of P38) abolished the inhibition of FGF21 on P38, while alteration was observed in the expression of RUNX-2. FGF21 inhibited VSMCs calcification via OPG/RANKL system, and through P38 andPI3K/AKT pathways.
血管钙化普遍存在，且与不良预后相关，目前尚无有效的治疗方法。成纤维细胞生长因子（FGF）-21在代谢和动脉粥样硬化方面的益处使其成为治疗血管钙化的一种有前景的治疗剂。我们通过在钙化培养基中培养大鼠血管平滑肌细胞（VSMC）9天，研究了FGF21对VSMC钙化的影响。在指定时间点，FGF21显著减弱了矿物质沉积和细胞凋亡。在FGF21存在的情况下，包括骨形态发生蛋白-2、碱性磷酸酶（ALP）、 runt相关转录因子（RUNX）-2和核因子-κB配体（RANKL）在内的成骨蛋白的表达水平下调，而骨保护素（OPG）的表达增加。敲低OPG显著削弱了FGF21对细胞凋亡以及包括半胱天冬酶-3和Bax在内的促凋亡基因和包括ALP、RUNX-2和RANKL在内的成骨促进标志物表达的抑制作用。此外，FGF21促进了AKT的磷酸化，但抑制了P38，而敲低OPG减弱了这些作用。LY29400（PI3K抑制剂）消除了PI3K/AKT的激活，SB203580（P38抑制剂）消除了FGF21对P38的抑制，同时观察到RUNX-2表达的改变。FGF21通过OPG/RANKL系统以及P38和PI3K/AKT途径抑制VSMC钙化。
