Hormonal control of plasminogen activator inhibitor-1 gene expression and production in human adipose tissue: Stimulation by glucocorticoids and inhibition by catecholamines

Plasma levels of type 1 plasminogen activator inhibitor (PAI-1), a risk fac tor for cardiovascular disease, are elevated in obese subjects, especially those with omental fat accumulation. We investigated the hormonal control o f PAI-1 gene expression and secretion in cultured human adipose tissue. We more particularly focused on the effects of glucocorticoids, insulin, cAMP, and catecholamines in explants from the omental region. The addition of de xamethasone to the culture medium increased PAI-1 secretion in a time-depen dent manner for up to 24 h. The stimulation by the glucocorticoid was prece ded by a a-fold rise in PAI-I messenger ribonucleic acid levels between 4-8 h of culture. The effectiveness of the glucocorticoid was concentration de pendent, with a half-maximal effect within a physiological range. This stim ulation was also observed in sc fat, but dexamethasone-stimulated as well a s basal PAI-1 secretion rates were always higher in omental fat. Unlike dex amethasone, 24-h insulin did not modify PAI-1 secretion while accelerating glucose consumption. In contrast, 24-h cAMP inhibited PAI-1 gene expression and protein production under basal conditions and in the presence of dexam ethasone. This inhibition was already detectable after 1 h and was maximal after 4 h at the level of gene expression. It occurred in both omental and sc adipose tissues. Importantly, epinephrine dose dependently inhibited PAI -1 parameters, an effect that was reproduced by isoproterenol. Dexamethason e- and cAMP-induced changes in PAI-1 messenger ribonucleic acid abundance m ere similar in explants and isolated fat cells. In isolated stromal-vascula r cells, only dexamethasone was effective. In conclusion, we provide eviden ce for a reciprocal regulation of PAI-1 by dexamethasone (positive effector ) and cAMP/catecholamines (negative effectors) in cultured human adipose ti ssue. The stimulation by glucocorticoids could contribute to enhanced produ ction of PAI-1 by adipose tissue and high plasma levels of PAI-1 associated with central obesity and thereby be a link between this disorder and cardi ovascular disease. Impaired inhibition by catecholamines could also contrib ute, as in vivo adipose tissue responses to these hormones are usually blun ted in obese individuals.