Gene expression analysis to identify mechanisms underlying heart failure susceptibility in mice and humans.

Academic Article

Abstract

  • Genetic factors are known to modulate cardiac susceptibility to ventricular hypertrophy and failure. To determine how strain influences the transcriptional response to pressure overload-induced heart failure (HF) and which of these changes accurately reflect the human disease, we analyzed the myocardial transcriptional profile of mouse strains with high (C57BL/6J) and low (129S1/SvImJ) susceptibility for HF development, which we compared to that of human failing hearts. Following transverse aortic constriction (TAC), C57BL/6J mice developed overt HF while 129S1/SvImJ did not. Despite a milder aortic constriction, impairment of ejection fraction and ventricular remodeling (dilation, fibrosis) was more pronounced in C57BL/6J mice. Similarly, changes in myocardial gene expression were more robust in C57BL/6J (461 genes) compared to 129S1/SvImJ mice (71 genes). When comparing these patterns to human dilated cardiomyopathy (1344 genes), C57BL/6J mice tightly grouped to human hearts. Overlay and bioinformatic analysis of the transcriptional profiles of C57BL/6J mice and human failing hearts identified six co-regulated genes (POSTN, CTGF, FN1, LOX, NOX4, TGFB2) with established link to HF development. Pathway enrichment analysis identified angiotensin and IGF-1 signaling as most enriched putative upstream regulator and pathway, respectively, shared between TAC-induced HF in C57BL/6J mice and in human failing hearts. TAC-induced heart failure in C57BL/6J mice more closely reflects the gene expression pattern of human dilated cardiomyopathy compared to 129S1/SvImJ mice. Unbiased as well as targeted gene expression and pathway analyses identified periostin, angiotensin signaling, and IGF-1 signaling as potential causes of increased HF susceptibility in C57BL/6J mice and as potentially useful drug targets for HF treatment.
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    Keywords

  • Cardiac function, Gene expression, Genetic background, Heart failure, Transverse aortic constriction, Animals, Cardiomyopathy, Dilated, Case-Control Studies, Disease Models, Animal, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease, Heart Failure, Hypertrophy, Left Ventricular, Male, Mice, 129 Strain, Mice, Inbred C57BL, Phenotype, Species Specificity, Transcriptome, Ventricular Function, Left, Ventricular Remodeling
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    Authorlist

  • Koentges C; Pepin ME; Müsse C; Pfeil K; Alvarez SVV; Hoppe N; Hoffmann MM; Odening KE; Sossalla S; Zirlik A
  • Start Page

  • 8
  • Volume

  • 113
  • Issue

  • 1