Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells.

The cysteine protease cathepsin L is one of the most potent mammalian elastases and collagenases, widely expressed at basal levels in most tested tissues and cell types, and regulated by pro-inflammatory stimuli. The inflammatory arterial diseases abdominal aortic aneurysm (AAA) and atherosclerosis involve extensive vascular remodeling that requires elastolysis and collagenolysis. This study examined the hypothesis that cathepsin L is over-expressed in human AAA and atherosclerotic lesions and its expression in vascular cell types found in these lesions is regulated by pro-inflammatory cytokines.

Cystatin C deficiency increases elastic lamina degradation and aortic dilatation in apolipoprotein E-null mice.

The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves substantial proteolysis of the arterial extracellular matrix. The lysosomal cysteine proteases can exert potent elastolytic and collagenolytic activity. Human atherosclerotic plaques have increased cysteine protease content and decreased levels of the endogenous inhibitor cystatin C, suggesting an imbalance that would favor matrix degradation in the arterial wall.

Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice.

Background: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine expressed widely by vascular cells. However, scant in vivo evidence supports direct participation of MIF in atherogenesis. Therefore, we investigated whether deficiency of MIF modulates atherosclerotic lesion formation and composition in low-density lipoprotein receptor-deficient (LDLr-/-) mice.

Lysosomal cysteine proteases in atherosclerosis.

Atherosclerosis is an inflammatory disease characterized by extensive remodeling of the extracellular matrix architecture of the arterial wall. Although matrix metalloproteinases and serine proteases participate in these pathologic events, recent data from atherosclerotic patients and animals suggest the participation of lysosomal cysteine proteases in atherogenesis. Atherosclerotic lesions in humans overexpress the elastolytic and collagenolytic cathepsins S, K, and L but show relatively reduced expression of cystatin C, their endogenous inhibitor, suggesting a shift in the balance between cysteine proteases and their inhibitor that favors remodeling of the vascular wall.

Increased expression of elastolytic cysteine proteases, cathepsins S and K, in the neointima of balloon-injured rat carotid arteries.

The matrix-degrading activity of several proteases are involved in the accelerated breakdown of extracellular matrix associated with vascular remodeling during the development of atherosclerosis and vascular injury-induced neointimal formation. Previous studies have shown that the potent elastolytic cysteine proteases, cathepsins S and K, are overexpressed in atherosclerotic lesions in human and animal models. However, the role of these cathepsins in vascular remodeling remains unclear.

Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice.

Human atherosclerotic lesions overexpress the lysosomal cysteine protease cathepsin S (Cat S), one of the most potent mammalian elastases known. In contrast, atheromata have low levels of the endogenous Cat S inhibitor cystatin C compared with normal arteries, suggesting involvement of this protease in atherogenesis. The present study tested this hypothesis directly by crossing Cat S-deficient (CatS(-/-)) mice with LDL receptor-deficient (LDLR(-/-)) mice that develop atherosclerosis on a high-cholesterol diet.

Macrophage migration inhibitory factor is associated with aneurysmal expansion.

Background: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine released mainly from macrophages and activated lymphocytes. Both atherosclerosis and abdominal aortic aneurysm (AAA) are inflammatory diseases tightly linked to the function of these cells. The correlation and contribution of MIF to these human diseases remain unknown, although a recent rabbit study showed expression of this cytokine in atherosclerotic lesions.