Submitted on August 29, 2007
Accepted on August 11, 2008
Exogenous Heat Shock Protein-70 Inhibits Cigarette Smoke Induced Intimal Thickening
Michiaki Matsumoto1, Paul C. Dimayuga1*, Charles Wang2, Jonathan Kirzner1, Miha Cercek1, Juliana Yano1, Kuang-Yuh Chyu1, Prediman K. Shah1, and Bojan Cercek1
1 Cardiology/Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States
2 Endocrinology/Medicine, Cedars-Sinai Medical Center, United States
* To whom correspondence should be addressed. E-mail: dimayugap{at}cshs.org.
Background: 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 micro-array analysis. In the current study, we investigated the role of extracellular HSP70 in carotid intimal thickening of mice exposed to cigarette smoke. Methods and Results: 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 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. Conclusion: 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.
