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STATE-OF-THE-ART PAPER

Retention and Activation of Blood-Borne Proteases in the Arterial Wall

Implications for Atherothrombosis

Inserm Unit 698, Cardiovascular Hematology, Bio-Engineering and Remodeling, CHU Xavier Bichat, Paris, France

Manuscript received November 29, 2005; revised manuscript received April 5, 2006, accepted April 18, 2006.

^_* Reprint requests and correspondence: Dr. Jean-Baptiste Michel, INSERM U698 "Cardiovascular Hematology, Bio-Engineering and Remodeling," Hôpital X. Bichat, 46, rue Henri Huchard, 75877 Paris Cedex 18, France. (Email: jbmichel{at}bichat.inserm.fr).

All forms of atheroma are characterized by a risk of arterial wall rupture leading to clinical complications. This involves medial and adventitial ruptures in abdominal aortic aneurysm (AAA) and intimal cap rupture in vulnerable atherothrombotic plaques. Extracellular proteases, including metalloproteinases, locally generated plasmin, and leukocyte elastase, are important molecular mediators of atheroma progression via their matrix degradation properties. The pathological evolution of AAA is linked to the biology of its associated mural thrombus. Indeed, in aneurysmal segments lined by a thrombus, the wall is thinner, the extracellular matrix more degraded, and the adventitial inflammatory response greater than in segments that are not. Several lines of evidence highlight the role of the thrombus, in AAA, as a reservoir of blood-borne proteases that conveys them from the lumen to the diseased wall. In stenosing atheroma, both previous and recent studies provide evidence that recurrent intraplaque hemorrhages play a dominant role in the evolution of the lesion toward vulnerability. In this review, we draw a parallel between the role of protease conveyance and activation of the mural thrombus in AAA and of intraplaque hemorrhages in stenosing atheroma. We hypothesize that intraplaque hemorrhages convey blood-borne proteases into lesions, where they are retained and activated upon thrombus/hematoma formation, thus contributing significantly to their deleterious action.

Abbreviations and Acronyms   AAA = abdominal aortic aneurysm   ECM = extracellular matrix   HSP = heat shock protein   MMP = matrix metalloproteinase   MRI = magnetic resonance imaging   SMC = smooth muscle cell   t-PA = tissue-type activators

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