Morange P E, Aubert J, Peiretti F, Lijnen H R, Vague P, Verdier M, Négrel R, Juhan-Vague I, Alessi M C
Laboratoire d'Hématologie, CR INSERM, Faculté de Médecine Timone, Marseille, France.
Diabetes. 1999 Apr;48(4):890-5. doi: 10.2337/diabetes.48.4.890.
Plasminogen activator inhibitor 1 (PAI-1) is likely to play a role in vascular disease, primarily in subjects with android obesity. It has been demonstrated that PAI-1 is overexpressed in adipose tissue from obese subjects and that visceral adipose tissue produced more PAI-1 than subcutaneous fat. In the present study, the effect of insulin and glucocorticoids, which are key mediators of adipose tissue metabolism, was examined in relation to PAI-1 synthesis by human adipose tissue explants (HAT), collagenase isolated human adipocytes (IHA), cultured human stromal cells (cSC), and differentiated adipocytes from the murine clonal cell line 3T3-F442A. A significant increase in PAI-1 antigen release (1.5-fold) from HAT was detectable after 16 h of treatment with insulin concentrations of at least 10(-8) mol/l. This was associated with a PAI-1 mRNA increase. Concomitant addition of insulin (10(-8) mol/l) to forskolin (5 x 10(-5) mol/l) reversed the decrease in PAI-1 antigen caused by forskolin alone. No effect on PAI-1 antigen was observed when insulin was incubated with IHA or cSC. 3T3 F442A cells were sensitive to insulin with a four- and twofold increase in PAI-1 antigen and mRNA levels, respectively, after 16 h of stimulation with 10(-8) mol/l. Dexamethasone (DXM) significantly enhanced PAI-1 antigen and mRNA expression by HAT (1.5- and 2.5-fold increase, respectively) at concentrations of at least 10(-8) mol/l. A higher stimulation was observed with IHA (sevenfold increase) and with the differentiated 3T3 F442 cell line. Cortisol was found to be less potent than DXM. No effect was observed when glucocorticoids were incubated with cSC. Coincubation of HAT with insulin (10(-7) mol/l) and DXM (10(-7) mol/l) led to an additive effect on PAI-1 synthesis. These results support the hypothesis that PAI-1 expression in human adipose tissue is controlled by insulin and glucocorticoids and may help to explain the increase in plasma PAI-1 levels observed in patients with android obesity.
纤溶酶原激活物抑制剂1（PAI-1）可能在血管疾病中发挥作用，主要是在具有腹部肥胖的受试者中。已经证明，PAI-1在肥胖受试者的脂肪组织中过度表达，并且内脏脂肪组织产生的PAI-1比皮下脂肪更多。在本研究中，研究了胰岛素和糖皮质激素（脂肪组织代谢的关键介质）对人脂肪组织外植体（HAT）、胶原酶分离的人脂肪细胞（IHA）、培养的人基质细胞（cSC）以及来自小鼠克隆细胞系3T3-F442A的分化脂肪细胞合成PAI-1的影响。用至少10^(-8) mol/l的胰岛素处理16小时后，可检测到HAT释放的PAI-1抗原显著增加（1.5倍）。这与PAI-1 mRNA增加有关。将胰岛素（10^(-8) mol/l）与福斯可林（5×10^(-5) mol/l）同时添加可逆转单独使用福斯可林引起的PAI-1抗原减少。当胰岛素与IHA或cSC孵育时，未观察到对PAI-1抗原的影响。用10^(-8) mol/l刺激16小时后，3T3 F442A细胞对胰岛素敏感，PAI-1抗原和mRNA水平分别增加了四倍和两倍。地塞米松（DXM）在至少10^(-8) mol/l的浓度下显著增强了HAT的PAI-1抗原和mRNA表达（分别增加1.5倍和2.5倍）。在IHA（增加七倍）和分化的3T3 F44细胞系中观察到更高的刺激。发现皮质醇的作用比DXM弱。当糖皮质激素与cSC孵育时，未观察到影响。将HAT与胰岛素（10^(-7) mol/l）和DXM（10^(-7) mol/l）共同孵育对PAI-1合成产生相加作用。这些结果支持以下假设，即人脂肪组织中PAI-1的表达受胰岛素和糖皮质激素控制，并且可能有助于解释在腹部肥胖患者中观察到的血浆PAI-1水平升高。
