Lesional overexpression of matrix metalloproteinase-9 promotes intraplaque hemorrhage in advanced lesions but not at earlier stages of atherogenesis.

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 (p=0.03). 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 (p=0.007). Colocalization with neovessels may point to neo-angiogenesis as a source for intraplaque hemorrhage. CONCLUSIONS: 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.

Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice.

OBJECTIVE: Although IL-18 has been implicated in atherosclerotic lesion development, little is known about its role in advanced atherosclerotic plaques. This study aims to assess the effect of IL-18 overexpression on the stability of preexisting plaques. METHODS AND RESULTS: Atherosclerotic lesions were elicited in carotid arteries of apolipoprotein E (apoE)-deficient mice (n=32) by placement of a perivascular collar. Overexpression of IL-18 was effected by intravenous injection of an adenoviral vector 5 weeks after surgery. Two weeks after transduction, lesions were analyzed histologically with regard to plaque morphology and composition or by real-time polymerase chain reaction. No difference in plaque size was detected between groups. In the Ad.IL-18-treated group, 62% of lesions displayed a vulnerable morphology or even intraplaque hemorrhage as compared with only 24% in the controls (P=0.037). In agreement, IL-18 overexpression reduced intimal collagen by 44% (P<0.003) and cap-to-core ratio by 41% (P<0.002). Although IL-18 did not affect the expression of collagen synthesis-related genes, it was found to enhance the collagenolytic activity of vascular smooth muscle cells in vitro, suggesting that the low collagen content is attributable to matrix degradation rather than to decreased synthesis. CONCLUSIONS: Systemic IL-18 overexpression markedly decreases intimal collagen content and cap thickness, leading to a vulnerable plaque morphology.