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Review
.2008 Dec;100(6):976-83.

Integration of non-SMAD and SMAD signaling in TGF-beta1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells

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Review

Integration of non-SMAD and SMAD signaling in TGF-beta1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells

Rohan Samarakoon et al. Thromb Haemost.2008 Dec.

Abstract

Overexpression of plasminogen activator inhibitor-1 (SERPINE1, PAI-1), the major physiological inhibitor of pericellular plasmin generation, is a significant causative factor in the progression of vascular disorders (e.g. arteriosclerosis, thrombosis, perivascular fibrosis) as well as a biomarker and a predictor of cardiovascular-disease associated mortality. PAI-1 is a temporal/spatial regulator of pericellular proteolysis and ECM accumulation impacting, thereby, vascular remodeling, smooth muscle cell migration, proliferation and apoptosis. Within the specific context of TGF-beta1-initiated vascular fibrosis and neointima formation, PAI-1 is a member of the most prominently expressed subset of TGF-beta1-induced transcripts. Recent findings implicate EGFR/pp60c-src-->MEK/ERK1/2 and Rho/ROCK-->SMAD2/3 signaling in TGF-beta1-stimulated PAI-1 expression in vascular smooth muscle cells. The EGFR is a direct upstream regulator of MEK/ERK1/2 while Rho/ROCK modulate both the duration of SMAD2/3 phosphorylation and nuclear accumulation. E-box motifs (CACGTG) in the PE1/PE2 promoter regions of the human PAI-1 gene, moreover, are platforms for a MAP kinase-directed USF subtype switch (USF-1-->USF-2) in response to growth factor addition suggesting that the EGFR-->MEK/ERK axis impacts PAI-1 expression, at least partly, through USF-dependent transcriptional controls. This paper reviews recent data suggesting the essential cooperativity among the EGFR-->MAP kinase cascade, the Rho/ROCK pathway and SMADs in TGF-beta1-initiated PAI-1 expression. The continued clarification of mechanistic controls on PAI-1 transcription may lead to new targeted therapies and clinically-relevant options for the treatment of vascular diseases in which PAI-1 dysregulation is a major underlying pathogenic feature.

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Figures

Figure 1
Figure 1. Potential contribution of overexpression of PAI-1 to cardiovascular disease (CVD)
TGF-β1, a major physiological regulator of PAI-1 expression, promotes extracellular matrix accumulation largely through the regulation of plasmin generation and MMP-mediated matrix degradation (via direct induction of PAI-1) as well as by inducing synthesis of matrix proteins (e.g. fibronectin, collagen) which, collectively, facilitate creation of a profibrotic state in vascular tissues. Increased PAI-1 expression by profibrotic and inflammatory factors (e.g. TGF-β, angiotensin) contributes to vascular thrombosis, by inhibition of fibrin degradation, neointimal expansion and arteriosclerosis, at least in part, by increasing VSMC proliferation and reducing VSMC apoptosis. PAI-1 elevation also attenuates plasmin-mediated matrix remodeling resulting in excessive extracellular matrix accumulation, a hallmark of perivascular fibrosis.
Figure 2
Figure 2. Model for TGF-β1-induced PAI-1 expression
Current data indicates thatTGF-β1 activates two distinct signaling pathways that initiate transcription of PAI-1. Rho/ROCK are required for maintenance of SMAD phosphorylation as well as ERK activation (through yet to be defined mechanisms) while the pp60c-src-activated EGFR (at theY845 site) signals to MEK-ERK initiating likely ERK/USF interactions resulting in USF phosphorylation and a subtype (USF-1→USF-2) switch at the PAI-1 PE1/PE2 E box sites. Collectively, these two promoter-level events stimulate high levels of PAI-1 in response to TGF-βR occupancy. The actual mechanism underlying EGFR activation in response toTGF-β1 is unknown but may involve direct recruitment ofsrc kinases to the EGFR or the processing and release of a membrane-anchored EGFR ligand (e.g. HB-EGF). Similarly, events associated with TGF-β1 stimulation of the RhoA/ROCK pathway are presently unclear. Rho/Rock may regulate the activity and/or function of the SMAD phosphatase PPM1A impacting, thereby, the duration of SMAD-dependent transcription of target genes such as PAI-1.
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