Elaboration of type-1 plasminogen activator inhibitor from adipocytes - A potential pathogenetic link between obesity and cardiovascular disease
Elaboration of type-1 plasminogen activator inhibitor from adipocytes - A potential pathogenetic link between obesity and cardiovascular disease
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DOI：
10.1161/01.cir.93.1.106
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发表时间：
1996-01-01
期刊：
影响因子：
37.8
通讯作者：
Fujii, S
中科院分区：
文献类型：
--
作者：
Lundgren, CH;Brown, SL;Fujii, S
背景已知肥胖易导致纤维蛋白溶解减弱，这归因于血浆中1型纤溶酶原激活物抑制剂（PAI-1）浓度增加，PAI-1是内源性纤维蛋白溶解的主要生理抑制剂。派-1是存在于新生内膜血管平滑肌细胞和脂质负载macrophage.Methods和结果-本研究旨在确定派-1的表达是否发生在脂肪组织以及，从而可能导致与肥胖相关的心血管风险增加。通过将3 T3-L1前脂肪细胞暴露于异丁基黄嘌呤（0.5mmol/L）和地塞米松（0.25 μ mol/L）7天，并与转化生长因子-β（TGF-β）孵育24小时，使其分化为脂肪细胞，已知TGF-β在几种细胞类型中增加派-1合成，并在血小板活化时从血小板释放。TGF-β在3 T3-L1衍生细胞的条件培养基中以浓度依赖性方式增加派-1活性，而不显著影响细胞增殖。Western blotting和S-35标记的派-1免疫沉淀结果表明，派-1活性的增加导致派-1蛋白的增加。北方印迹显示派-1 mRNA的增加先于条件培养基中派-1活性和蛋白的积累。此外，TGF-β（10 ng/g体重）在体内给药增加派-1活性在小鼠血浆和派-1 mRNA的表达在小鼠脂肪tissue.Conclusions增加血浆派-1活性在肥胖的人受试者可能会导致派-1释放从增加的质量的脂肪组织，特别是在与血栓形成和加工的TGF-β从血小板α-颗粒进入循环。PAI-I升高可能通过使血栓形成和血栓溶解之间的平衡向血栓形成方向移动，从而使血管的管腔表面暴露于与微血栓相关的有丝分裂原，从而加重血管疾病。
Background Obesity is known to predispose to attenuated fibrinolysis attributable to increased concentrations in plasma of type-1 plasminogen activator inhibitor (PAI-1), the primary physiological inhibitor of endogenous fibrinolysis. PAI-1 is present in neointimal vascular smooth muscle cells and lipid-laden macrophages.Methods and Results The present study was designed to determine whether PAI-1 expression occurs in adipose tissue as well, thereby potentially contributing to increased cardiovascular risk associated with obesity. 3T3-L1 preadipocytes were differentiated into adipocytes by exposing them to isobutylxanthine (0.5 mmol/L) and dexamethasone (0.25 mu mol/L) over 7 days and incubated for 24 hours with transforming growth factor-beta (TGF-beta), known to augment PAI-1 synthesis in several cell types and to be released from platelets when they are activated. TGF-beta increased PAI-1 activity in the conditioned media of the 3T3-L1-derived cells in a concentration-dependent fashion without significantly affecting cell proliferation. Western blotting and immunoprecipitation of S-35-labeled PAI-1 showed that the increased PAI-1 activity paralleled increased PAI-1 protein. Northern blotting showed that increased PAI-1 mRNA preceded increased accumulation of PAI-1 activity and protein in the conditioned media. Furthermore TGF-beta (10 ng/g body wt) administered in vivo increased PAI-1 activity in mouse plasma and PAI-1 mRNA expression in mouse adipose tissue.Conclusions Increased plasma PAI-1 activity in obese human subjects may result from PAI-1 release from an increased mass of adipose tissue, particularly in association with thrombosis and elaboration of TGF-P from platelet oc-granules into the circulation. The increased PAI-I may exacerbate vascular disease by shifting the balance between thrombosis and thrombolysis toward thrombosis and consequently exposing luminal surfaces of vessels to mitogens associated with microthrombi over protracted intervals.