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

Basic Res Cardiol. 2017 Dec 29;113(1):8. doi: 10.1007/s00395-017-0666-6. Print 2018 Jan 8.


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.

Keywords: Cardiac function; Gene expression; Genetic background; Heart failure; Transverse aortic constriction.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathy, Dilated / complications
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / physiopathology
  • Case-Control Studies
  • Disease Models, Animal
  • Disease Progression
  • Gene Expression Profiling / methods
  • Gene Expression Regulation*
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease
  • Heart Failure / genetics*
  • Heart Failure / physiopathology
  • Hypertrophy, Left Ventricular / complications
  • Hypertrophy, Left Ventricular / genetics*
  • Hypertrophy, Left Ventricular / physiopathology
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Phenotype
  • Species Specificity
  • Transcriptome
  • Ventricular Function, Left / genetics*
  • Ventricular Remodeling / genetics