title: Gene expression profiling during the transition to failure in TNF-alpha over-expressing mice demonstrates the development of autoimmune myocarditis.
abstract: Transgenic mice with cardiac-specific over-expression of tumor necrosis factor-alpha (TNF1.6) progress to dilated heart failure. A significant inflammatory response precedes functional deterioration, and may contribute to cardiac damage in this model. To evaluate the underlying molecular mechanisms, we assessed the gene expression in six groups of mouse hearts defined by age, gender, and phenotype (n = 3/group) using Affymetrix microarray analysis. Phenotype was defined as compensated (in young TNF1.6) or decompensated (in older TNF1.6) via echocardiogram. Of the >1000 transcripts altered in the compensated hearts (fold change > 2, P < 0.05 vs. wild-type (WT)), 102 were identified as immune response genes, 20 of which function in antigen presentation and processing. When comparing the compensated and decompensated hearts, >50 genes were differentially regulated, including seven immunoglobulin genes. Real-time reverse transcriptase-polymerase chain reaction and cDNA microarray confirmed the Affymetrix data. Mac3+ macrophages, CD4+ T and CD45/B220+ B-cells were identified in both compensated and decompensated hearts. However, a large amount of IgG was found deposited in areas devoid of B-lymphocytes in the myocardium of decompensated TNF1.6 mice; no such accumulation was seen in the compensated or age-matched controls. Furthermore, nuclei density analyses showed a two-fold increase in the myocardium of both compensated and decompensated TNF1.6 mice (vs. WT). This study suggests that TNF-alpha over-expression activates not only the inflammatory response, but also humoral immune responses within the transgenic hearts. The autoimmune response occurs concomitantly with cardiac decompensation and may participate in triggering the transition to failure in TNF1.6 mice.
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Suite 813 College Building, 1025 Walnut Street, Philadelphia, PA 19107, USA. zhong.tang@jefferson.edu
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Tang
authors.forename: Brian S
authors.initials: BS
authors.lastname: McGowan
authors.forename: Sally A
authors.initials: SA
authors.lastname: Huber
authors.forename: Charles F
authors.initials: CF
authors.lastname: McTiernan
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.forename: Saul
authors.initials: S
authors.lastname: Surrey
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Maura A
authors.initials: MA
authors.lastname: Diamond
authors.forename: Dwayne S
authors.initials: DS
authors.lastname: Wyre
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D009202:Cardiomyopathies; D002467:Cell Nucleus / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004452:Echocardiography; D005260:Female; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000378:metabolism*; D006984:Hypertrophy; D007074:Immunoglobulin G / Q000737:chemistry; D007150:Immunohistochemistry; D007249:Inflammation; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009205:Myocarditis / Q000276:immunology*; D009206:Myocardium / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D018075:RNA, Complementary / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; D007074:Immunoglobulin G; D018075:RNA, Complementary; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D017493:Leukocyte Common Antigens