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Am J Physiol Regul Integr Comp Physiol 295: R1320-R1327, 2008. First published August 13, 2008; doi:10.1152/ajpregu.00624.2007
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ENVIRONMENTAL PHYSIOLOGY

Exogenous heat shock protein-70 inhibits cigarette smoke-induced intimal thickening

Michiaki Matsumoto,1,* Paul C. Dimayuga,1,* Charles Wang,2 Jonathan Kirzner,1 Miha Cercek,1 Juliana Yano,1 Kuang-Yuh Chyu,1 Prediman K. Shah,1 and Bojan Cercek1

1Division of Cardiology and Atherosclerosis Research Center, Burns and Allen Research Institute, and 2Division of Endocrinology, Department of Medicine, Cedars-Sinai Medical Center/David Geffen School of Medicine at University of California at Los Angeles

Submitted 29 August 2007 ; accepted in final form 8 August 2008

Cigarette smoke is associated with increased carotid intimal thickening or stroke. Preliminary work showed that exposure to smoke resulted in a 4.5-fold reduction of heat shock protein-70 (HSP70) expression in spleens of mice using gene microarray analysis. In the current study, we investigated the role of extracellular HSP70 in carotid intimal thickening of mice exposed to cigarette smoke. Intimal thickening was induced by placement of a cuff around the right carotid artery of mice. Cuff injury resulted in increased HSP70 mRNA expression in carotid arteries that persisted for 21 days. Cigarette smoke exposure decreased arterial HSP70 expression and significantly increased intimal thickening compared with mice exposed to air. Treatment of mice exposed to cigarette smoke with intravenous recombinant HSP70 attenuated intimal thickening through reduced phosphorylated extracellular signal-regulated kinase (pERK) expression in the arterial wall. In vitro experiments with rat aortic smooth muscle cells confirmed that recombinant HSP70 decreases pERK and proliferating cell nuclear antigen (PCNA) expression in cells exposed to cigarette smoke extract and H2O2. Our study suggests that decreased expression of arterial HSP70 is an important mechanism by which exposure to cigarette smoke augments intimal thickening. The effects of recombinant HSP70 suggest a role for extracellular HSP70.

arterial injury; oxidative stress; extracellular signal-regulated kinase


Address for reprint requests and other correspondence: P. C. Dimayuga, Davis Bldg., Rm. 1064, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048 (e-mail: DimayugaP{at}cshs.org)






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