Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists.
Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists.
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DOI：
10.1161/circresaha.117.312418
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发表时间：
2018-05-11
影响因子：
20.1
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Shen J;Zhang N;Lin YN;Xiang P;Liu XB;Shan PF;Hu XY;Zhu W;Tang YL;Webster KA;Cai R;Schally AV;Wang J;Yu H
血管钙化（VC）是动脉粥样硬化疾病严重程度的标志。激素在调节钙化中起着重要作用;雌激素和甲状旁腺激素发挥相反的作用，前者缓解VC，后者加重VC。探讨生长激素释放激素（GHRH）及其激动剂（GHRH-A）对小鼠VC阻断作用的影响。年轻的成年骨保护素缺乏（OPG−/−）小鼠每天皮下注射GHRH-A（MR 409），持续4周。MR 409处理小鼠的骨钙化显著减少，这是由于碱性磷酸酶（ALP）活性显著降低和转录因子（包括成骨标志物基因Runx 2及其下游因子骨粘连蛋白和骨钙素）表达显著减少。GHRH-A的作用机制在从人和小鼠睾丸分离的平滑肌细胞（SMC）中进行了剖析。GHRH或MR 409可抑制成骨培养基（OM）诱导的SMC钙化，ALP活性和Runx 2表达降低可证明这一点。MR 409对钙化的抑制作用可被GHRH拮抗剂MIA 602或GHRH受体选择性siRNA部分逆转。MR 409处理可诱导胞浆cAMP及其靶点蛋白激酶A（PKA）升高，从而阻断NADPH氧化酶活性并减少活性氧（ROS）的产生，从而阻断NFκB（p65）的磷酸化，NFκB（p65）是RANKL-Runx 2/ALP成骨程序中的关键中间体。PKA选择性siRNA或化学抑制剂H89消除了MR 409的这些有益作用。GHRH-A通过靶向PKA和NFκB（p65）之间的串扰以及通过抑制诱导Runx 2基因和ALP的ROS产生来控制SMC中的骨生成。炎症介导的骨生成因此被阻断。GHRH-A可能代表一种新的调节VC的药理学策略。
Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. So far no treatment strategies have been developed to regulate clinical VC. To investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model. Young adult osteoprotegerin deficient (OPG−/−) mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409 treated mice were paralleled by markedly lower alkaline phosphatase (ALP) activity and a dramatic reduction in the expression of transcription factors including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH-A was dissected in smooth muscle cells (SMCs) isolated from human and mouse aortas. Calcification of SMCs induced by osteogenic medium (OM) was inhibited in the presence of GHRH or MR409, as evidenced by reduced ALP activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor selective siRNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A (PKA) which in turn blocked NADPH oxidase activity and reduced production of reactive oxygen species (ROS), thus blocking the phosphorylation of NFκB (p65), a key intermediate in the RANKL-Runx2/ALP osteogenesis program. A PKA-selective siRNA or the chemical inhibitor H89 abolished these beneficial effects of MR409. GHRH-A controls osteogenesis in SMCs by targeting cross talk between PKA and NFκB (p65) and through the suppression of ROS production that induces the Runx2 gene and ALP. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC.