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EXPERIMENTAL STUDY

Accelerated intimal thickening in carotid arteries of balloon-injured rats after immunization against heat shock protein 70

Jacob George, MD^*, Shai Greenberg, MSc^*, Iris Barshack, MD, Madhavir Singh, PhD, Sara Pri-Chen, PhD^*, Shlomo Laniado, MD^* and Gad Keren, MD^*,*

^* Department of Cardiology and the Cardiovascular Research Laboratory, Tel Aviv Medical Center, Tel Aviv, Israel
Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel
GBF-Braunschweig, Braunschweig, Germany

Manuscript received December 19, 2000; revised manuscript received June 14, 2001, accepted July 12, 2001.

^* Reprint requests and correspondence: Dr. Gad Keren, Department of Cardiology and the Cardiovascular Research Laboratory, Ichilov Hospital, Elias Sourasky, Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv, Israel
kereng{at}tasmc.health.gov.il

OBJECTIVES

The goal of this study was to test the hypothesis that induction of an immune response to heat shock protein (Hsp) 70 would increase intimal thickening in a rat carotid-injury model.

BACKGROUND

Restenosis resulting from intimal thickening poses a major limitation to the long-term success of coronary angioplasty. Several studies have proposed that infectious agents increase restenosis. Heat shock proteins are highly conserved structures, produced by all cells in response to nonspecific forms of stress. Infectious agents are known to contain Hsp70, which is markedly immunogenic and can elicit a strong immune response.

METHODS

To investigate whether Hsp70 immunity can affect neointimal thickening, we immunized rats with either Hsp70 (n = 11), bovine serum albumin ([BSA] n = 9) or with a control adjuvant (n = 10). Three weeks later, rats were boosted using the same regimen to achieve a sustained immune response to Hsp70 after which carotid injury was applied to all animals.

RESULTS

Arterial injury was associated with upregulation of Hsp70, 3, 7 and 14 days after induction of the injury as evidenced by Western blotting and immunohistochemistry. Intimal area and intimal/medial ratio was significantly increased in Hsp70-immunized rats in comparison with BSA or control-injected rats.

CONCLUSIONS

Our results imply that upregulation of Hsp70 in balloon-injured arteries can serve as a target for anti-Hsp70 immune response, thereby facilitating enhanced intimal thickening. These observations may provide a possible mechanism that explains the accelerated intimal thickening that has been associated with the occurrence of infectious pathogens.

Abbreviations and Acronyms   BSA = bovine serum albumin   ELISA = enzyme-linked immunosorbent assay   Hsp = heat shock protein   IFA = incomplete Freund’s adjuvant   IgG = immunoglobulin G   PBS = phosphate-buffered saline   PI = protease inhibitor   SMC = smooth muscle cell   TBS = Tris-buffered saline

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