Upregulation of lysyl oxidase in vascular smooth muscle cells by cAMP: Role for adenosine receptor activation

Lysyl oxidase (LO) is a key participant in the accumulation of insoluble fi bers of elastin and collagen by virtue of its role in the initiation of the covalent cross-linkages between and within individual molecules comprising these fibers. In view of the essential role played by LO in the accumulati on of the fibrotic components of occlusive arterial lesions in atherosclero sis, identification of the signaling molecules which can affect the express ion of the LO gene in vascular smooth muscle is of considerable interest. I n the present report, we describe evidence for the role of the second messe nger, cAMP, in the modulation of the levels of LO in vascular smooth muscle cells. Elevated intracellular cAMP induces the transcription of the LO gen e, as revealed by Northern blot analysis and nuclear run on assays. Transie nt transfection experiments performed with the wild-type LO promoter and wi th this promoter mutated at a consensus CREB site, located within the regio n -100 to -93 base pairs relative to the start of transcription, indicate t hat cAMP-induced transcriptional activation is partially due to the presenc e of th is CREB site with in the promoter. Activation of stimulatory adenos ine receptors in vascular smooth muscle cells with 5'-N-ethylcarboxamido ad enosine (NECA) increases cAMP, LO mRNA, and enzyme activity. These findings point to the importance of cAMP signaling, potentially initiated by a vari ety of physiological agents, in the upregulation of LO expression in Vascul ar smooth muscle cells. (C) 1999 Wiley-Liss, Inc.