Functional matrix metalloproteinase-9 polymorphism (C-1562T) associated with abdominal aortic aneurysm

Jones, Gregory T.; Phillips, Victoria; Harris, Eugenie L.; Rossaak, Jeremy; Rij, André M. van

doi:10.1016/s0741-5214(03)01027-9

Cited by 106 publications

(71 citation statements)

References 27 publications

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“…20,26 MMP-9 plasma levels are raised in patients with acute coronary syndromes 10,27 and high-expressing MMP-9 polymorphisms are associated with increased risk for cardiovascular events. 9,28 Conversely, apoE Ϫ/Ϫ /MMP-9 Ϫ/Ϫ mice displayed more characteristics of plaque vulnerability than their MMP-9 ϩ/ϩ littermates. 14 In this study, MMP-9 was overexpressed in pre-existing plaques at an intermediate and advanced stage of progression to evaluate the effect on both plaque morphology and stability.…”

Section: Control Nϭ12mentioning

confidence: 99%

Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis

Nooijer

Verkleij

Thüsen

et al. 2006

ATVB

198

119

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Background-Matrix metalloproteinase-9 (MMP-9) is involved in atherosclerosis and elevated MMP-9 activity has been found in unstable plaques, suggesting a crucial role in plaque rupture. This study aims to assess the effect of MMP-9 on plaque stability in apolipoprotein E-deficient mice at different stages of plaque progression. Methods and Results-Atherosclerotic lesions were elicited in carotid arteries by perivascular collar placement. MMP-9 overexpression in intermediate or advanced plaques was effected by intraluminal incubation with an adenovirus (Ad.MMP-9). A subset was coincubated with Ad.TIMP-1. Mock virus served as a control. Plaques were analyzed histologically. In intermediate lesions, MMP-9 overexpression induced outward remodeling, as shown by a 30% increase in media size (pϭ0.03). In both intermediate and advanced lesions, prevalence of vulnerable plaque morphology tended to be increased. Half of MMP-9 -treated lesions displayed intraplaque hemorrhage, whereas in controls and the Ad.MMP-9/Ad.TIMP-1 group this was 8% and 16%, respectively (pϭ0.007). Colocalization with neovessels may point to neo-angiogenesis as a source for intraplaque hemorrhage. Conclusion-These data show a differential effect of MMP-9 at various stages of plaque progression and suggest that lesion-targeted MMP-9 inhibition might be a valuable therapeutic modality in stabilizing advanced plaques, but not at earlier stages of lesion progression. Key Words: adenovirus Ⅲ atherosclerosis Ⅲ metalloproteinases Ⅲ remodeling Ⅲ vulnerable plaque M atrix metalloproteinase (MMP) family members are enzymes with activity against extracellular matrix (ECM) constituents and are linked to atherosclerosis and plaque rupture. Because plaque disruption is a frequent cause of acute coronary syndromes 1,2,3 and MMPs are believed to degrade the ECM in the fibrous cap, 4,5 these enzymes might prove to be relevant targets for therapeutic intervention.However, the evidence that links these proteases to plaque destabilization is largely based on retrospective observations. Elevated MMP levels, among which is MMP-9, were found in unstable areas in carotid endarterectomy specimens. 6,7 Several promoter polymorphisms are correlated to coronary artery disease and to lesion complexity. 8,9 Also, elevated MMP-9 plasma levels can be detected in patients with acute coronary syndromes. 10,11 Taken together, this suggests that MMP-9 is causally involved in plaque destabilization, although the underlying mechanism remains unclear. One report showed that MMP-9 overexpression leads to thrombosis by stimulating release of matrix-bound tissue factor in balloon-injured coronaries. 12 Conversely, targeted gene disruption of MMP-9 in mice impaired smooth muscle cell (SMC) migration and led to collagen accumulation. 13 In vitro, MMP-9 deficiency impaired the contracting capacity of collagen, indicating that MMP-9 not only is important for SMC migration and matrix degradation but also plays a role in ECM organization. 13 Notwithstanding these observations, direct evidence fo...

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Section: Control Nϭ12mentioning

confidence: 99%

Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis

Nooijer

Verkleij

Thüsen

et al. 2006

ATVB

198

119

View full text Add to dashboard Cite

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“…5 Variations in genes that regulate ECM stability have been described to increase the susceptibility to AAA. Association has been reported with matrix-metalloproteinases 6,7 and their inhibitors (tissue inhibitors of metalloproteinases). 7 However, attempts to replicate these associations in different populations have led to conflicting results.…”

Section: Introductionmentioning

confidence: 99%

Association of the TGF-β receptor genes with abdominal aortic aneurysm

et al. 2009

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Abdominal aortic aneurysm (AAA) is a multifactorial condition. The transforming growth factor b (TGF-b) pathway regulates vascular remodeling and mutations in its receptor genes, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysm (TAA). The TGF-b pathway may be involved in aneurysm development in general. We performed an association study by analyzing all the common genetic variants in TGFBR1 and TGFBR2 using tag single nucleotide polymorphisms (SNPs) in a Dutch AAA case-control population in a two-stage genotyping approach. In stage 1, analyzing 376 cases and 648 controls, three of the four TGFBR1 SNPs and nine of the 28 TGFBR2 SNPs had a Po0.07. Genotyping of these SNPs in an independent cohort of 360 cases and 376 controls in stage 2 confirmed association (Po0.05) for the same allele of one SNP in TGFBR1 and two SNPs in TGFBR2. Joint analysis of the 736 cases and 1024 controls showed statistically significant associations of these SNPs, which sustained after proper correction for multiple testing (TGFBR1 rs1626340 OR 1.32 95% CI 1.11-1.56 P¼0.001 and TGFBR2 rs1036095 OR 1.32 95% CI 1.12-1.54 P¼0.001 and rs4522809 OR 1.28 95% CI 1.12-1.46 P¼0.0004). We conclude that genetic variations in TGFBR1 and TGFBR2 associate with AAA in the Dutch population. This suggests that AAA may develop partly by similar defects as TAA, which in the future may provide novel therapeutic options.

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“…24 These polymorphisms have been associated with cardiovascular diseases. 12,23,[25][26][27][28] Therefore, our hypothesis was that these polymorphisms could interact with HIV infection or with HAART and modify MMP-9 levels in HIV patients, possibly affecting their cardiovascular risk.…”

Section: Introductionmentioning

confidence: 99%

A genetic polymorphism of matrix metalloproteinase 9 (MMP-9) affects the changes in circulating MMP-9 levels induced by highly active antiretroviral therapy in HIV patients

et al. 2009

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We examined whether two functional polymorphisms (g.À1562C4T and g.À90(CA)14-24) in the matrix metalloproteinase (MMP)-9 gene or MMP-9 haplotypes affect the circulating levels of pro-MMP-9 and pro-MMP-9/TIMP-1 (tissue inhibitor of metalloproteinase-1) ratios in AIDS patients, and modulate alterations in these biomarkers after highly active antiretroviral therapy (HAART). We studied 82 patients commencing HAART. Higher pro-MMP-9 concentrations and pro-MMP-9/TIMP-1 ratios were found in CT/TT patients compared with CC patients. HAART decreased pro-MMP-9 levels and pro-MMP-9/TIMP-1 ratios in CT/TT patients, it did not modify pro-MMP-9 levels and it increased pro-MMP-9/TIMP-1 ratios in CC patients. The g.À90(CA)14-24 polymorphism, however, produced no significant effects. Moreover, we found no significant differences in HAARTinduced changes in plasma pro-MMP-9, TIMP-1 and pro-MMP-9/TIMP-1 ratios when different MMP-9 haplotypes were compared. These findings suggest that the g.À1562C4T polymorphism affects pro-MMP-9 levels in patients with AIDS and modulates the alterations in pro-MMP-9 levels caused by HAART, thus possibly affecting the risk of cardiovascular complications.

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Functional matrix metalloproteinase-9 polymorphism (C-1562T) associated with abdominal aortic aneurysm

Abstract: This study provides further evidence to support the role of MMP-9 in the pathogenesis of AAA, and indicates that the MMP9 C-1562T functional polymorphism may represent a genetic component contributing to susceptibility to this vascular disease.

Cited by 106 publications

References 27 publications

Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis

Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis

Association of the TGF-β receptor genes with abdominal aortic aneurysm

A genetic polymorphism of matrix metalloproteinase 9 (MMP-9) affects the changes in circulating MMP-9 levels induced by highly active antiretroviral therapy in HIV patients

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