Selective Inhibition of Matrix Metalloproteinase-13 Increases Collagen Content of Established Mouse Atherosclerosis

Abstract

Evidence has linked collagen loss with the onset of acute coronary events. Objective This study tested the hypothesis that selective MMP-13 collagenase inhibition increases collagen content in already established and nascent mouse atheromata. Methods and Results In vitro and in situ experiments documented the selectivity and efficacy of an orally available MMP-13 inhibitor (MMP13i-A). In vivo observations monitored macrophage accumulation and MMP-13 activity using molecular imaging. After 10 weeks of MMP13i-A treatment, apoE-/- mice with evolving or established lesions exhibited reduced MMP-13 activity without affecting macrophage content, measured either by intravital microscopy or fluorescence reflectance imaging. Histological analysis indicated that MMP13-iA did not affect plaque size, or macrophage or smooth-muscle cell accumulation. Administration of MMP13i-A to mice with evolving or established atheromata substantially increased plaque interstitial collagen content in the intima and locally in the fibrous cap, compared to vehicle-treated controls. Analysis of collagen revealed thicker collagen fibers within the plaques of treated groups. Conclusions Pharmacological MMP-13 inhibition yields collagen accumulation in plaques (a feature associated in humans with resistance to rupture), even in established plaques. This study of considerable clinical relevance furnishes new mechanistic insight into regulation of the plaque's extracellular matrix, and validates molecular imaging for studying plaque biology.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Pharmacological MMP-13 inhibition yields collagen accumulation in plaques (a feature associated in humans with resistance to rupture), even in established plaques (Quillard et al, 2011).…”

Atherosclerotic Plaque Destabilization

“…41 Other MMPs such as MMP-8 and MMP-13 have also been suggested to control plaque macrophage and collagen content. 42,43 In addition to macrophages, neutrophils are also an important source of MMP-8 and MMP-9 and may contribute to plaque instability. In fact, lesional MMP-8 and MMP-9 levels 44 were mainly associated with increased intraplaque neutrophil infiltration and were inversely correlated with plaque stability traits.…”

Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells

“…It is suggested that increased matrix is associated with plaque stability, whereas matrix degradation weakens the fibrous cap and increases its susceptibility to rupture. (4,29,55) The S carotid plaques are usually associated with ruptured atherosclerotic plaques with thin fibrous cap (23,24,42). The risk for atherosclerotic plaque rupture in S plaques is partially mediated by degradation of ECM by MMPs (10, 21, 33, 39).…”