Plasminogen Activator Inhibitor Type 1 Increases Neointima Formation in Balloon-Injured Rat Carotid Arteries

Abstract

Background-Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are associated with myocardial infarction, atherosclerosis, and restenosis. PAI-1 is increased in atherosclerotic arteries and failed vein grafts. No experimental data, however, support a causal relationship between elevated PAI-1 expression and vascular lesions. Paradoxically, data generated in PAI-1 knockout mice suggest that PAI-1 might decrease lesion formation after arterial injury and that PAI-1 gene transfer might prevent restenosis. Methods and Results-Using the rat carotid balloon injury model and a PAI-1-expressing adenoviral vector, we tested whether elevated arterial PAI-1 expression would alter neointima formation. Compared with control-transduced arteries, neointima formation in PAI-1-transduced arteries was initially retarded. By 14 days, however, the intimas of PAI-1-transduced arteries were significantly larger than intimas of control-transduced arteries (1.6Ϯ0.1ϫ10 5 versus 1.2Ϯ0.1ϫ10 5 m 2 , nϭ18 to 19, PϽ0.03). PAI-1 expression in individual arteries correlated with increased cell proliferation at 4 and 8 days after injury (Rϭ0.6, PϽ0.02 and PϽ0.006). PAI-1 expression also correlated with fibrin(ogen) accumulation (Rϭ0.77, PϽ0.001), and fibrin(ogen) accumulation correlated strongly with proliferation (Rϭ0.86, PϽ0.00001). Conclusions-Increased expression of PAI-1 in the artery wall promotes neointima growth after balloon injury. Therefore, despite encouraging data generated in other animal models, PAI-1 is not a promising agent for gene therapy to prevent restenosis. Moreover, our data associate elevated PAI-1 expression with fibrin(ogen) accumulation and increased cell proliferation. These data suggest a mechanism to explain the association between elevated PAI-1 expression and the progression of arterial disease.

Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

“…Consistent with these results, de Waard et al 30 reported an increase in neointima formation in PAI-1 À/À mice after carotid artery ligation; and Allaire et al 31 showed that local overexpression of PAI-1 prevented aneurysm development in a xenograft model. In contrast to these findings, Ploplis and Castellino 32 reported that copper-cuff-induced neointima formation was decreased in PAI-1 À/À mice compared to wild type controls and DeYoung et al 33 reported that overexpression of PAI-1 gene in the carotid artery enhanced neointima growth following balloon injury in rats. In a recent study, transplantation of wild type bone marrow in PAI-1 deficient mice significantly suppressed neointima formation after vascular injury with ferric chloride.…”

Glycolaldehyde-derived advanced glycation end products (glycol-AGEs)-induced vascular smooth muscle cell dysfunction is regulated by the AGES-receptor (RAGE) axis in endothelium

“…Moreover, PAI-1 is upregulated by various stimuli in cultured ECs, including TNF-a and IL-1b. Increased expression of PAI-1 attenuates apoptosis of VSMCs but is associated with significant proliferation after injury to arteries in rats (DeYoung et al 2001). In addition, in the co-cultured system with HUVECs and VSMCs, a significant increase in both PAI-1 secretion from HUVECs and intracellular PAI-1 expression in VSMCs were observed (Gallicchio et al 1994).…”

Increased Expression of Elastolytic Cysteine Proteases, Cathepsins S and K, in the Neointima of Balloon-Injured Rat Carotid Arteries

“…Although the rat carotid artery balloon-injury model does not represent human restenosis with complete accuracy, many studies using this model have been performed to reveal the mechanisms of vascular remodeling induced by balloon injury. 7,8,11 After balloon injury, the SMCs must modulate elastin-rich matrix to penetrate the internal elastic lamina from the media to the intima to form the neointimal lesion. This process of SMC migration is critically dependent on the action of extracellular proteases.…”

“…[7][8][9][10] Abundant evidence now supports a potential role for these two proteolytic systems in vascular remodeling. 7,8,11 However, recent studies using mice with targeted gene deletion and inhibitors of these proteases have suggested that other proteolytic Both cathepsin S and K protein levels in the medial and the neointimal cell layers of rat carotid artery between day 7 and 14 after injury. A and C: Representative Western blot of the medial and the neointima cellular extracts analyzed with both affinity-purified antibody to cathepsin S or K. Data represent results from at three separate determinations.…”

“…[7][8][9][10] This is supported by findings that MMPs and plasminogen activator levels are elevated after balloon injury to rat carotid arteries. 7,8,11 However, previous observations have suggested that the even effective inhibition of MMPs and serine proteases might not sufficiently arrest neointima formation. [12][13][14][15] Cathepsins, lysosomal proteases within the papain superfamily, are thought to generally reside in and function optimally within acidic lysosomes.…”