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Infection and Immunity, January 2006, p. 152-159, Vol. 74, No. 1
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.1.152-159.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Trypanosoma cruzi Infection Induces Proliferation of Vascular Smooth Muscle Cells

Ghada S. Hassan,¹ Shankar Mukherjee,² Fnu Nagajyothi,² Louis M. Weiss,^2,3 Stefka B. Petkova,^2, Cecilia J. de Almeida,¹ Huan Huang,² Mahalia S. Desruisseaux,^2,3 Boumediene Bouzahzah,¹ Richard G. Pestell,⁴ Chris Albanese,⁴ George J. Christ,⁵ Michael P. Lisanti,¹ and Herbert B. Tanowitz^2,3*

Department of Molecular Pharmacology, The Albert Einstein Cancer Center, and Departments of,¹ Pathology,² Medicine, Albert Einstein College of Medicine, Bronx, New York,³ Department of Oncology and the Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.,⁴ Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina⁵

Received 31 August 2005/ Returned for modification 4 October 2005/ Accepted 20 October 2005

Trypanosoma cruzi infection causes cardiomyopathy and vasculopathy. Previous studies have demonstrated that infection of human umbilical vein endothelial and smooth muscle cells resulted in activation of extracellular signal-regulated kinase (ERK). In the present study, smooth muscle cells were infected with trypomastigotes, and immunoblot analysis revealed an increase in the expression of cyclin D1 and proliferating cell nuclear antigen (PCNA), important mediators of smooth muscle cell proliferation. Interestingly, after infection, the expression of caveolin-1 was reduced in both human umbilical vein endothelial cells and smooth muscle cells. Immunoblot and immunohistochemical analyses of lysates of carotid arteries obtained from infected mice revealed increased expression of PCNA, cyclin D1, its substrate, phospho-Rb (Ser780), and phospho-ERK1/2. The expression of the cyclin-dependent kinase inhibitor p21^Cip1/Waf1, caveolin-1, and caveolin-3 was reduced in carotid arteries obtained from infected mice. There was an increase in the abundance of pre-pro-endothelin-1 mRNA in the carotid artery and aorta from infected mice. The ET_A receptor was also elevated in infected arteries. ERK activates endothelin-1, which in turn exerts positive feedback activating ERK, and cyclin D1 is a downstream target of both endothelin-1 and ERK. There was significant incorporation of bromodeoxyuridine into smooth muscle cell DNA when treatment was with conditioned medium obtained from infected endothelial cells. Taken together, these data suggest that T. cruzi infection stimulates smooth muscle cell proliferation and is likely a result of the upregulation of the ERK-cyclin D1-endothelin-1 pathway.

Editor: W. A. Petri, Jr.

Present address: Jackson Laboratories, Bar Harbor, Maine.