Biological significance of decreased HSP27 in human atherosclerosis.
OBJECTIVE
Because culprit atherosclerotic plaques contain proteases, we hypothesized that the diminished heat shock protein 27 (HSP27) released by atherosclerotic plaques could be due to proteolysis. We assessed the role of HSP27 in human vascular smooth muscle cells (VSMCs) under proteolytic injury.


RESULTS
Active plasmin is present in culprit atherosclerotic plaques. Recombinant HSP27 was cleaved by plasmin and this effect was prevented by different inhibitors. Fragments and aggregated forms of HSP27 appeared after incubation of mammary control endarteries with plasmin. Coincubation of atherosclerotic plaques with recombinant HSP27 or mammary endarteries led to HSP27 proteolysis. After incubation of VSMCs with plasmin, HSP27 was overexpressed, phosphorylated, aggregated, and redistributed from the cytoskeleton to the cytosol, nucleus, and cell membrane. Plasmin-induced VSMC apoptosis was significantly higher in VSMCs treated by HSP27 siRNA. Immunohistochemical analysis of atherosclerotic plaques showed that plasmin(ogen) and apoptotic cells are localized in the core/shoulder whereas HSP27 and VSMCs are mainly expressed in the cap/media.


CONCLUSIONS
Extracellular HSP27 can be degraded by enzymes released from atherosclerotic plaques and may reflect a proteolytic imbalance. Intracellular HSP27 downregulation decreases VSMCs resistance to proteolytically-induced apoptosis. HSP27 might play a pivotal role in the prevention of plaque instability and rupture.
Inserm, U698, University of Paris 7 and CHU X-Bichat, Paris, France.
Jose Luis
JL
Martin-Ventura
Valentin
V
Nicolas
Xavier
X
Houard
Luis Miguel
LM
Blanco-Colio
Anne
A
Leclercq
Jesús
J
Egido
Roger
R
Vranckx
Jean-Baptiste
JB
Michel
Olivier
O
Meilhac
D017209:Apoptosis; D050197:Atherosclerosis / Q000503:physiopathology*; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D005341:Fibrinolysin / Q000378:metabolism / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D046509:Tissue Culture Techniques
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D005341:Fibrinolysin