Different expression of MMPs/TIMP-1 in human atherosclerotic lesions. Relation to plaque features and vascular bed

Abstract

Background: Proteolytic imbalance might determine arterial remodeling and plaque destabilization in atherosclerotic vessels. The aim of this study was to examine differences in the patterns of metalloproteinases (MMPs) and MMP inhibitor (TIMP-1) expression in advanced human atheromas, both in relation to the plaque features and the vascular bed involved. Methods and results: Immunohistochemistry for MMP-1, -3, -9 and TIMP-1 as well as the collagen content were measured in vascular sections from patients undergoing peripheral revascularization (carotid n = 11, femoral n = 23) and aorto-coronary bypass surgery (mammary arteries n = 20, as controls). Increased expression of all MMPs was detected in atherosclerotic as compared with control sections (P<0.01). Aneurismal plaques showed a significant increase of MMP-1 and-3 and a reduction in total collagen (P<0.05) in relation to occlusive lesions. Calcification areas in atherosclerotic plaques were consistently associated with increased TIMP-1 expression (P<0.01). Finally, MMP-9 expression was higher in occlusive lesions from carotid than femoral arteries (P<0.01). Conclusions: Aneurysm lesions expressed higher MMP-1 and-3 expression than occlusive plaques, and MMP-9 was mainly detected in carotid as compared with femoral arteries. TIMP-1 was associated with arterial calcification. These differences in the MMPs/TIMP-1 expression might determine the evolution of advanced atherosclerotic plaques and contribute to its vulnerability.

Collagens in the progression and complications of atherosclerosis

“…151 Thus, it is tempting to speculate a mechanism where the expression of type II collagen in the intima can induce a feed-forward matrix remodeling mechanism to drive the process of atherosclerotic calcification. In human atherosclerotic lesions, the endogenous MMP inhibitor, TIMP-1, is highly expressed adjacent to calcified foci, 152 further alluding to a role for the MMP family in the calcification process. Whether MMPs can be targeted to prevent calcification of the atherosclerotic intima remains to be tested, although broad-spectrum MMP inhibition with doxycycline successfully prevented vitamin D-induced calcification of the media in rats.…”

Matrix metalloproteinases in cardiovascular disease

“…In the presence of infection, inflammation or excessive mechanical stress, the MMP activity can further hasten the disintegration of the fibrous cap, leading to plaque rupture and its consequences MMP-3 in the advancing edges of the atherosclerotic plaque (8). The MMPs found are often associated with the presence of inflammatory cells, such as macrophages or T lymphocytes (9).…”

“…Interestingly, the natural inhibitors of MMP, the TIMPs, are also found in the atherosclerotic plaque (9). However, at sites where increased TIMPs are present, there is often associated vascular calcification (8). This may mean that vascular calcification is nature's way of stabilizing the remodelling process, and may be a consequence of TIMP action over that of MMPs.…”

Relationship Between Multiple Plasma Biomarkers and Vulnerable Plaque Determined by Virtual Histology Intravascular Ultrasound

“…[4][5][6][7][8][9] It is known that matrix metalloproteinases-2 and -9 (MMP-2, -9), tissue inhibitor of metalloproteinase-1 (TIMP-1), adiponectin, and macrophage migration inhibitory factor (MIF) correlate with either plaque destabilization or stabilization. [10][11][12][13][14] However, there are only a few studies of the relationship between plasma biomarkers and plaque characteristics determined by imaging. 15 Therefore, we investigated whether levels of biomarkers that are known to be associated with plaque vulnerability, such as MMP-2, MMP-9, TIMP-1, adiponectin and MIF, can be used as predictors of ruptured plaque or VH-TCFA as determined by 3-vessel VH-IVUS study.…”