Abstract
There is an unmet need for treatments to reduce abdominal aortic aneurysm (AAA) progression. Vascular smooth muscle cell (VSMC) apoptosis precipitates AAA formation, whereas VSMC proliferation repairs the vessel wall. We previously demonstrated that over-expression of EC4-Fc (truncated N-cadherin), or deletion of matrix-metalloproteinase-7 (Mmp-7) reduced VSMC apoptosis in mouse atherosclerotic plaques. Additionally, MMP-7 promotes VSMC apoptosis by cleavage of N-cadherin. We investigated their combined effect on AAA formation. Increased apoptosis and proliferation were observed in human AAA (HAAA) sections compared to normal aortae (HA). This coincided with increased MMP-7 activity and reduced N-cadherin protein levels in HAAA sections compared to HA. Using a mouse model of aneurysm formation, we showed that the combination of Mmp-7 deletion and EC4-Fc overexpression significantly increased AAA severity. Medial apoptosis and proliferation were both significantly reduced in these mice compared to control mice. In vitro, MMP-7 inhibition and EC4-Fc administration significantly supressed human aortic VSMC apoptosis (via activation of PI-3 kinase/Akt signalling) and proliferation. In conclusion, combined Mmp-7 deletion and systemic over-expression of EC4-Fc reduced both proliferation and apoptosis. Reduced proliferation-mediated repair over-rides any benefit of reduced apoptosis, increasing aneurysm severity. Future studies should therefore focus on retarding VSMC apoptosis whilst promoting VSMC proliferation.
Highlights
IntroductionNegative nuclei are blue. Arrows indicate some positive cells
Positive cells are brown, negative nuclei are blue
In line with the proposition that matrix metalloproteinase-7 (MMP-7) cleaves N-cadherin, western blot analysis of tissue lysates showed that protein levels of full length N-cadherin were significantly lower in human AAA (HAAA) compared to healthy aorta (HA), whilst more N-cadherin fragment was observed in the HAAA samples (Fig. 1d)
Summary
Negative nuclei are blue. Arrows indicate some positive cells. We have previously shown that soluble N-cadherin (SNC), and a smaller truncation of SNC, called EC4-Fc, significantly increase features of atherosclerotic plaque stability[14,15]. These studies showed that SNC-Fc and EC4-Fc are able to modulate VSMC proliferation, migration and apoptosis[14,15]. Our group have since shown that MMP-7 promotes VSMC apoptosis by cleavage of N-cadherin and may modulate atherosclerotic plaque development and rupture[17]. Broad-spectrum MMP inhibition is known to reduce proliferation by limiting N-cadherin shedding from the cell surface[18]. The aims of this study were firstly, to investigate the relevance of our target pathways and molecules in human AAA (HAAA) samples, secondly to investigate the effects of EC4-Fc over-expression and Mmp-7 deletion on AAA development and progression, using the mouse Ang-II induced aneurysm model and thirdly, to study the effects of EC4 administration and MMP7 inhibition in vitro
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