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

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

Author information

1
Cardiology and Angiology I, Heart Center, Freiburg University, Hugstetter Str. 55, 79106, Freiburg, Germany.
2
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, 901 19th Street South, BMR2 Rm 506, Birmingham, AL, 35294, USA.
3
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
4
Institute for Clinical Chemistry and Laboratory Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
5
Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
6
Institute of Experimental and Clinical Pharmacology, BIOSS Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
7
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, 901 19th Street South, BMR2 Rm 506, Birmingham, AL, 35294, USA. adamwende@uabmc.edu.
8
Cardiology and Angiology I, Heart Center, Freiburg University, Hugstetter Str. 55, 79106, Freiburg, Germany. heiko.bugger@universitaets-herzzentrum.de.
9
Faculty of Medicine, University of Freiburg, Freiburg, Germany. heiko.bugger@universitaets-herzzentrum.de.

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.

KEYWORDS:

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

PMID:
29288409
PMCID:
PMC5764079
DOI:
10.1007/s00395-017-0666-6
[Indexed for MEDLINE]
Free PMC Article

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