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Archives of cardiovascular diseases
Volume 102, n° S1
page 24 (mars 2009)
Doi : 10.1016/S1875-2136(09)72181-3
Themes et posters

B010 Inhibition of furin by PAI-1: a potential role in metabolic syndrome
 

D. Bernot, O. Hadadeh, D. Bastelica, G. Nalbone, M.-C. Alessi, F. Peiretti
Inserm U626, Marseille, France 

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Metabolic Syndrome (MS) predisposes to type 2 diabetes (T2D) and coronary heart disease (CAD). Elevated levels of the serpin PAI-1 are observed in MS, and epidemiological studies evidenced an association between increased PAI-1 levels, the risk of CAD and more recently T2D. However, it is still unknown whether PAI-1 is causally involved.

To answer this point, we studied the potential effect of PAI-1 on Furin convertase, focusing on the processing of two Furin substrates: the insulin proreceptor (proIR) and proADAM-17.

In Furin-defective LoVo cells, proIR was weakly processed, due to the lack of endogenous Furin activity. Overexpression of Furin greatly enhanced the maturation of proIR, which was inhibited by a synthetic convertase inhibitor. In Furin-transfected LoVo cells, expression of PAI-1 (wild-type or stabilized mutant) reduced proIR maturation. ProIR maturation was neither altered by the addition of exogenous recombinant PAI-1 to LoVo cells overexpressing Furin, nor by the coculture of Furin-only expressing cells with PAI-1-only expressing cells. These results suggest an intracellular inhibitory effect of PAI-1 on Furin.

We also observed that PAI-1 expression in LoVo cells moderately inhibited Furin-dependent maturation of proADAM-17/TACE, an enzyme involved in the shedding of TNF and its receptors (TNFRs). As a result, the Furin-activated cleavage of TNF and both TNFRs by ADAM-17 was significantly reduced by PAI-1 expression.

In conclusion, our results suggest a potential role of PAI-1 as a Furin inhibitor, which could give to PAI-1 a causative role in MS by regulating both insulin and TNF pathways.

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