Published online before print March 30, 2006, doi: 10.1161/01.ATV.0000220108.97208.67
© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Biological Significance of Decreased HSP27 in Human Atherosclerosis
From Inserm (L.M.-V., V.N., X.H., A.L., R.V., J.-B.M., O.M.), U698 and University of Paris 7 and CHU X-Bichat, Paris, France; and the Vascular Research Laboratory (L.M.B.-C., J.E.), Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
Correspondence to Olivier Meilhac, PhD, INSERM U698 "Cardiovascular Hematology, Bio-Engineering and Remodeling," Hôpital X, Bichat, 46, rue Henri Huchard, 75877 Paris Cedex 18, France. E-mail meilhac{at}bichat.inserm.fr
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.
Methods and 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.
Decreased HSP27 is a potential sign of atherosclerosis, although its biological significance remains undefined. Extracellular HSP27 is proteolyzed by enzymes released from atherosclerotic plaques. Intracellular HSP27 downregulation decreases VSMC resistance to proteolytic injury. Decreased HSP27 may reflect proteolytic imbalance occurring during pathological vascular remodeling processes.
Key Words: anoikis • atherosclerosis • HSP27 • plasmin • proteases
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