Department of Cardiology , University of Wales College of Medicine , Cardiff , Wales , U.K.
Biochem J 315 ( Pt 1 ) : 335-42 ( 1996)
Abstract
The migration and proliferation of vascular smooth muscle cells ( SMCs ) during neointima formation in atherosclerosis and angioplasty restenosis is mediated by certain growth factors and cytokines , one action of which may be to promote basement-membrane degradation .
To test this hypothesis further , the effects of such growth factors and cytokines on the synthesis of two basement-membrane-degrading metalloproteinases , namely the 72 kDa gelatinase ( MMP-2 , gelatinase A ) and the 95 kDa gelatinase ( MMP-9 , gelatinase B ) and three tissue inhibitors of metalloproteinases ( TIMPs ) was studied in primary cultured rabbit aortic SMCs .
Expression of the 95 kDa gelatinase was increased by phorbol myristate acetate , foetal calf serum , thrombin and interleukin-1alpha ( IL-1alpha ) ; platelet-derived growth factor ( PDGF ) BB alone had no effect but acted synergistically with IL-1alpha .
A selective protein kinase C inhibitor , Ro 31-8220 , abolished induction of the 95 kDa gelatinase .
In contrast , none of the agents tested modulated the synthesis of the 72 kDa gelatinase .
We conclude that maximal up-regulation of 95 kDa gelatinase expression requires the concerted action of growth factors and inflammatory cytokines mediated , in part , by a protein kinase C-dependent pathway .
TIMP-1 and TIMP-2 were highly expressed , and their synthesis was not affected by growth factors or cytokines .
Expression of TIMP-3 mRNAs was , however , increased by PDGF and transforming growth factor beta , especially in combination .
Divergent regulation of gelatinase and TIMP expression implies that either net synthesis or net degradation of basement membrane can be mediated by appropriate combinations of growth factors and cytokines .