Biology Reference
In-Depth Information
smooth muscle cells and endothelial cells. Cardiovascular diseases are character-
ized by the unwanted degradation of the ECM. MMPs contribute to the ECM
degradation in cardiovascular diseases (Keeling et al.
2005
;L jnen
2003
;
Newby
2006
) but cannot account for all of it. Due to their potent collagenolytic
and elastolytic potential, cysteine cathepsins have been implicated (Liu et al.
2004
; Lutgens et al.
2007
). An increased expression of cathepsins has been found
in different cell types in atherosclerotic lesions. Smooth muscle cells express
cathepsins K, L, and S, macrophages express cathepsins B, K, S, and V, and
epithelial cells express cathepsins K and S (Buhling et al.
2004b
). Increased
expression of cathepsins L, K, S, and V is thought to lead to ECM degradation.
Cathepsin K has a strong elastolytic potential at neutral pH and collagenolytic
potential at a slightly acidic pH (Bromme et al.
1996
), cathepsin V has been shown to
be the most potent elastase known so far (Yasuda et al.
2004
), cathepsin S is a strong
elastase and is active at neutral pH (Shi et al.
1992
), whereas human cathepsin L is a
relatively weak elastase. It should be noted that mouse cathepsin L, which is more
closely related to human cathepsin V than to human cathepsin L, is a potent
elastase (Yasuda et al.
2004
). In cultured fibroblasts, elastin degradation takes
place both intracellularly and extracellularly by cathepsin K, S, and V (Yasuda
et al.
2004
).
In cultured smooth muscle cells, cathepsin S inhibition prevents the majority
of elastin degradation and cell invasion through an elastin gel (Cheng et al.
2006
;
Sukhova et al.
1998
). Cathepsin K, S, and L deficiencies in
Apo
mice all
revealed a reduction in medial elastic lamina breakdown, suggesting the involve-
ment of these elastolytic cathepsins in atherosclerotic blood vessel damage
(de Nooijer et al.
2009
; Kitamoto et al.
2007
; Lutgens et al.
2006
; Samokhin
et al.
2008
). Figure
2.6a
depicts a multinucleated cell expressing cathepsin K
adjacent to an elastic lamina break. A high-resolution electron microscopy image
reveals the accumulation of intercellular vesicles at the cell membrane close to
the elastin break site (Fig.
2.6b
). Cathepsin levels are also increased in aortic
aneurisms and neovascularization and have been linked to ECM degradation (Shi
et al.
2003
). Cathepsin K expression appears to be regulated by shear stress
suggesting that it has a role in arterial remodeling (Lutgens et al.
2006
;Platt
et al.
2007
). The role of cathepsins in atherosclerosis has been recently reviewed
(Lutgens et al.
2007
).
ECM degradation by cathepsins may also regulate angiogenesis. The degrada-
tion of the terminal end of collagen XVIII results in the creation of the antiangio-
genic factor endostatin (Platt et al.
2007
). Collagen XVIII is a component of
vascular and epithelial basement membrane. Cathepsins L, B, and K have been
shown to be capable of creating endostatin proteins, with cathepsin L the most
efficient protease and cathepsin K the least efficient at releasing peptides (Felbor
et al.
2000
; Platt et al.
2007
). The proteases were also shown to degrade the
endostatin fragment with cathepsins L and B the most efficient. Certain MMPs
can create endostatin but cannot degrade it; therefore, the ability of cathepsins
to create and degrade endostatin factors could have implications for tumor meta-
stasis and growth.
/
