Salusin-β Promotes Vascular Calcification via Nicotinamide Adenine Dinucleotide Phosphate/Reactive Oxygen Species-Mediated Klotho Downregulation
Salusin-β Promotes Vascular Calcification via Nicotinamide Adenine Dinucleotide Phosphate/Reactive Oxygen Species-Mediated Klotho Downregulation
复制标题
Salusin-beta 通过烟酰胺腺嘌呤二核苷酸磷酸/活性氧介导的 Klotho 下调促进血管钙化
DOI：
10.1089/ars.2019.7723
复制
发表时间：
2019-12-20
影响因子：
6.6
通讯作者：
Tang, Haiyang
中科院分区：
文献类型：
--
作者：
Sun, Haijian;Zhang, Feng;Tang, Haiyang
目的：血管钙化（VC）是心血管疾病的标志性特征，也是发病率和死亡率的重要危险因素。Salusin-beta在高血压、动脉粥样硬化和糖尿病中发挥心血管调节作用。本研究旨在探讨salusin-beta在VC进展中的作用及其下游信号机制。结果如下：在维生素D3和尼古丁诱导的VC大鼠睾丸和与钙化培养基孵育的血管平滑肌细胞（VSMCs）中Salusin-beta表达增加。Salusin-beta敲低显著降低VC，而Salusin-beta过表达在体外和体内均加重VC。salusin-β过表达促进VSMC骨软骨样转变，降低Klotho蛋白水平，增强Ras相关的C3肉毒毒素底物1（Rac 1）活性和p47 phox向细胞膜的转位，增加烟酰胺腺嘌呤二核苷酸磷酸[NAD（P）H]氧化酶亚单位的表达和活性氧（ROS）的产生;然而，salusin-beta缺乏症起着相反的作用。由salusin-beta诱导的钙化和下调的Klotho蛋白水平可通过ROS清除剂N-乙酰基-L-半胱氨酸、氯化二苯碘铵[含黄素酶（包括NAD（P）H氧化酶）的抑制剂]或NAD（P）H氧化酶（NOX）-2，p22 phox或p47 phox的基因敲减恢复，但不受NOX-1和NOX-4敲减的影响。Klotho基因敲减减弱了salusin-beta缺乏对VSMC钙化的保护作用。相比之下，外源Klotho改善了由salusin-beta过表达诱导的VC和ROS产生的发展。创新：Salusin-beta是VC中的关键调节剂。结论：Salusin-beta通过激活NAD（P）H/ROS介导的Klotho下调来调节VC，表明Salusin-beta可能是治疗VC的新靶点。
Aims: Vascular calcification (VC) is a hallmark feature of cardiovascular disease and a significant risk factor for morbidity and mortality. Salusin-beta exerts cardiovascular regulating effects in hypertension, atherosclerosis, and diabetes. The present study was designed to examine the roles of salusin-beta in the progression of VC and its downstream signaling mechanisms. Results: Salusin-beta expression in both the aortas of VC rats induced by vitamin D3 and nicotine and vascular smooth muscle cells (VSMCs) incubated with calcifying media was increased. Salusin-beta knockdown remarkably reduced VC, whereas overexpression of salusin-beta exacerbated VC both in vitro and in vivo. Overexpression of salusin-beta promoted the VSMC osteochondrogenic transition, decreased Klotho protein levels, enhanced Ras-related C3 botulinum toxin substrate 1 (Rac1) activity and the translocation of p47phox to the membrane, increased the expression of nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase subunits and the production of reactive oxygen species (ROS) with or without calcifying media; however, salusin-beta deficiency played the opposite roles. The calcification and downregulated Klotho protein levels induced by salusin-beta were restored by ROS scavenger N-acetyl-l-cysteine, diphenyleneiodonium chloride [an inhibitor of flavin-containing enzyme, including NAD(P)H oxidase], or gene knockdown of NAD(P)H oxidase (NOX)-2, p22phox, or p47phox but were not affected by NOX-1 and NOX-4 knockdown. Klotho knockdown attenuated the protective effect of salusin-beta deficiency on VSMC calcification. By contrast, exogenous Klotho ameliorated the development of VC and ROS generation induced by salusin-beta overexpression. Innovation: Salusin-beta is a critical modulator in VC. Conclusion: Salusin-beta regulates VC through activation of NAD(P)H/ROS-mediated Klotho downregulation, suggesting that salusin-beta may be a novel target for treatment of VC.