TY - JOUR
T1 - Reversion of gene expression alterations in hearts of mice with chronic chagasic cardiomyopathy after transplantation of bone marrow cells
AU - Soares, Milena B.P.
AU - Lima, Ricardo S.
AU - Souza, Bruno S.F.
AU - Vasconcelos, Juliana F.
AU - Rocha, Leonardo L.
AU - Dos Santos, Ricardo Ribeiro
AU - Iacobas, Sanda
AU - Goldenberg, Regina C.
AU - Lisanti, Michael P.
AU - Iacobas, Dumitru A.
AU - Tanowitz, Herbert B.
AU - Spray, David C.
AU - De Campos Carvalho, Antonio C.
N1 - Funding Information:
Financial support for these studies was provided by the National Institutes of Health (HL-73732, HD-32573, AI-076248), CAPES, CNPq, FINEP, FAPERJ and FAPESB. R.C.S.G. and L.R. were supported by a Fogarty International Training Grant D43TW007129. The authors thank Carine Machado for technical assistance.
PY - 2011/5/1
Y1 - 2011/5/1
N2 - Chronic chagasic cardiomyopathy is a leading cause of heart failure in Latin American countries, being associated with intense inflammatory response and fibrosis. We have previously shown that bone marrow mononuclear cell (BMC) transplantation improves inflammation, fibrosis and ventricular diameter in hearts of mice with chronic Chagas disease. Here we investigated the transcriptomic recovery induced by BMC therapy by comparing the heart transcriptomes of chagasic mice treated with BMC or saline with control animals. Out of the 9,390 unique genes quantified in all samples, 1,702 had their expression altered in chronic chagasic hearts compared to those of normal mice. Major categories of significantly upregulated genes were related to inflammation, fibrosis and immune responses, while genes involved in mitochondrion function were downregulated. When BMC-treated chagasic hearts were compared to infected mice, 96% of the alterations detected in infected hearts were restored to normal levels, although an additional 109 genes were altered by treatment. Transcriptomic recovery, a new measure that considers both restorative and side effects of treatment, was remarkably high (84%). Immunofluorescence and morphometric analyses confirmed the effects of BMC therapy in the pattern of inflammatory-immune response and expression of adhesion molecules. In conclusion, by using large-scale gene profiling for unbiased assessment of therapeutic efficacy we demonstrate immunomodulatory effects of BMC therapy in chronic chagasic cardiomyopathy and identify potentially relevant factors involved in the pathogenesis of the disease that may provide new therapeutic targets.
AB - Chronic chagasic cardiomyopathy is a leading cause of heart failure in Latin American countries, being associated with intense inflammatory response and fibrosis. We have previously shown that bone marrow mononuclear cell (BMC) transplantation improves inflammation, fibrosis and ventricular diameter in hearts of mice with chronic Chagas disease. Here we investigated the transcriptomic recovery induced by BMC therapy by comparing the heart transcriptomes of chagasic mice treated with BMC or saline with control animals. Out of the 9,390 unique genes quantified in all samples, 1,702 had their expression altered in chronic chagasic hearts compared to those of normal mice. Major categories of significantly upregulated genes were related to inflammation, fibrosis and immune responses, while genes involved in mitochondrion function were downregulated. When BMC-treated chagasic hearts were compared to infected mice, 96% of the alterations detected in infected hearts were restored to normal levels, although an additional 109 genes were altered by treatment. Transcriptomic recovery, a new measure that considers both restorative and side effects of treatment, was remarkably high (84%). Immunofluorescence and morphometric analyses confirmed the effects of BMC therapy in the pattern of inflammatory-immune response and expression of adhesion molecules. In conclusion, by using large-scale gene profiling for unbiased assessment of therapeutic efficacy we demonstrate immunomodulatory effects of BMC therapy in chronic chagasic cardiomyopathy and identify potentially relevant factors involved in the pathogenesis of the disease that may provide new therapeutic targets.
KW - Cardiomyopathy
KW - Cell transplantation
KW - Chagas disease
KW - Fibrosis
KW - Inflammation
KW - Microarray
KW - Trypanosoma cruzi
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UR - http://www.scopus.com/inward/citedby.url?scp=79955612827&partnerID=8YFLogxK
U2 - 10.4161/cc.10.9.15487
DO - 10.4161/cc.10.9.15487
M3 - Article
C2 - 21467843
AN - SCOPUS:79955612827
SN - 1538-4101
VL - 10
SP - 1448
EP - 1455
JO - Cell Cycle
JF - Cell Cycle
IS - 9
ER -
