Role of elastolytic cathepsins in vascular remodeling

摘要

Background:We now appreciate that the pathogenesis of atherosclerosis and abdominal aortic aneurysms (AAA) involves breakdown of extracellular matrix (ECM).We recently implicated certain elastolytic cysteine-dependent cathepsins in these pathological processes Results:We demonstrated over-expression of cathepsins S and K inhuman atheroma and AAA, and colocalized cathepsin S-positive medial smooth muscle cells (SMC) with sites of internal elastic lamina fragmentation.Moreover, depletion of cystatin C, the most abundant endogenous cysteine protease inhibitor, characterizes both atherosclerotic and aneurysmal lesions.To test directly the role of cathepsin S in atherogenesis, we studied targeted disruption of the cathepsin S gene in atherosclerosis-prone LDLr~(-/-) mice consuming a western diet. Cathepsin S deficiency significantly decreased atherosclerosis. Better -preserved elastin in the tunica media of cathepsin S-deficient mice likely reflected the diminished elastolytic activity in cathepsin S~(-/-)^sSMC (p< 0 0001) compared with wild-type SMC.These mice had fewer SMC and less collagen in theii intimal lesions, probably because SMC migration requires degradation of elastin. Conclusions:Our findings in situ, in vitro and in vivo establish an important role for cathepsins in vascular remodeling.