Mechanisms of Hypoxic Regulation of Plasminogen Activator Inhibitor-1 Gene Expression in Keloid Fibroblasts

Abstract

Keloids are an excessive accumulation of extracellular matrix. Although numerous studies have shown elevated plasminogen activator inhibitor-1 (PAI-1) levels in keloid ¢broblasts compared with those of normal skin. Their speci¢c mechanisms involved in the di¡erential expression of PAI-1 in these cell types. In this study, the upregulation of PAI-1 expression is demonstrated in keloid tissues and their derived dermal ¢broblasts, attesting to the persistence, if any, of fundamental di¡erences between in vivo and in vitro paradigms. We further examined the mechanisms involved in hypoxia-induced regulation of PAI-1 gene in dermal ¢broblast derived from keloid lesions and associated clinically normal peripheral skins from the same patient. Primary cultures were exposed to an environmental hypoxia or desferroxamine. We found that the hypoxia-induced elevation of PAI-1 gene appears to be regulated at both transcriptional and post-transcriptional levels in keloid ¢broblasts. Furthermore, our results showed a consistent elevation of HIF-1a protein level in keloid tissues compared with their normal peripheral skin controls, implying a potential role as a biomarker for local skin hypoxia. Treatment with antisense oligonucleotides against hypoxia-inducible factor 1a (HIF-1a) led to the downregulation of steady-state levels of PAI-1 mRNA under both normoxic and hypoxic conditions. Conceivably, our results suggest that HIF-1a may be a novel therapeutic target to modulate the scar ¢brosis process. Key words: hypoxia/half-life/desferroxamine/HIF-1a/antisense J Invest Dermatol 121:1005 ^1012, 2003