Angiotensin II and Its Metabolites Stimulate PAI-1 Protein Release From Human Adipocytes in Primary Culture

Abstract

Abstract —Plasminogen activator inhibitor (PAI)-1 is the main inhibitor of the fibrinolytic system and was recently shown to be produced by adipose cells. Obesity is associated with an increased production and release of PAI-1 protein. The aim of this study was to investigate the role of angiotensin (Ang) II and its degradation products for PAI-1 release from human adipose cells. For this purpose, we used the model of in vitro differentiated human adipocytes in primary culture. Exposure of human adipocytes to Ang II resulted in a dose- and time-dependent stimulation of PAI-1 release into the culture medium. The maximum effect of Ang II was found at a concentration of 10 −5 mol/L for 48 hours, increasing PAI-1 release by 276±53% compared with control cultures ( P <0.05). This stimulation was preceded by an increase in specific PAI-1 mRNA copies by 65±12% ( P <0.05), with a maximum after 6 hours. Incubation of adipocytes with 10 −5 mol/L Ang III and Ang IV, respectively, also resulted in a stimulation of PAI-1 release into the medium by 195±60% ( P <0.05) and 142±24% ( P <0.05), respectively, compared with control cultures. Addition of the angiotensin-receptor subtype 1 (AT 1 ) blocker candesartan abolished the stimulatory action of Ang II and its metabolites, indicating that this effect is mediated by AT 1 . Addition of the AT 1 blocker alone to unstimulated cultures reduced PAI-1 release by 41%±25% ( P <0.05), suggesting that endogenous Ang II synthesis contributes to PAI-1 secretion from adipose tissue in an autocrine/paracrine manner. In conclusion, Ang II and its metabolites promote PAI-1 production and release by human fat cells and may contribute to the impairment of the fibrinolytic system typical for obesity. AT 1 receptor blockade reduces basal and abolishes Ang II–stimulated PAI-1 release from human adipocytes.