Trypanosoma cruzi infection induces proliferation of vascular smooth muscle cells.
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.
Hassan
Ghada S
GS
Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Mukherjee
Shankar
S
Nagajyothi
Fnu
F
Weiss
Louis M
LM
Petkova
Stefka B
SB
de Almeida
Cecilia J
CJ
Huang
Huan
H
Desruisseaux
Mahalia S
MS
Bouzahzah
Boumediene
B
Pestell
Richard G
RG
Albanese
Chris
C
Christ
George J
GJ
Lisanti
Michael P
MP
Tanowitz
Herbert B
HB
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002339:Carotid Arteries / Q000201:enzymology; D022461:Caveolins / Q000096:biosynthesis / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D014355:Chagas Disease / Q000378:metabolism* / Q000473:pathology*; D019938:Cyclin D1 / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism / Q000469:parasitology; D019332:Endothelin-1 / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008809:Mice, Inbred C3H; D009131:Muscle, Smooth, Vascular / Q000469:parasitology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000469:parasitology* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000502:physiology; D012322:RNA Precursors / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000502:physiology*
D022461:Caveolins; D019332:Endothelin-1; D018809:Proliferating Cell Nuclear Antigen; D012322:RNA Precursors; D044022:Receptor, Endothelin A; D019938:Cyclin D1; D048049:Extracellular Signal-Regulated MAP Kinases; D001973:Bromodeoxyuridine