Comparative Phenotypic Assessment of Cardiac Pathology, Physiology, and Gene Expression in C3H/HeJ, C57BL/6J, and B6C3F1/J Mice

Abstract

Human cardiomyopathies often lead to heart failure, a major cause of morbidity and mortality in industrialized nations. Described here is a phenotypic characterization of cardiac function and genome-wide expression from C3H/HeJ, C57BL/6J, and B6C3F1/J male mice. Histopathologic analysis identified a low-grade background cardiomyopathy (murine progressive cardiomyopathy) in eight of nine male C3H/HeJ mice (age nine to ten weeks), but not in male C57BL/6J and in only of ten male B6C3F1/J mice. The C3H/HeJ mouse had an increased heart rate and a shorter RR interval compared to the B6C3F1/J and C57BL/6J mice. Cardiac genomic studies indicated the B6C3F1/J mice exhibited an intermediate gene expression phenotype relative to the 2 parental strains. Disease-centric enrichment analysis indicated a number of cardiomyopathy-associated genes were induced in B6C3F1/J and C3H/HeJ mice, including Myh7, My14, and Lmna and also indicated differential expression of genes associated with metabolic (e.g., Pdk2) and hypoxic stress (e.g. Hif1a). A novel coexpression and integrated pathway network analysis indicated Prkaa2, Pdk2, Rhoj, and Sgcb are likely to play a central role in the pathophysiology of murine progressive cardiomyopathy in C3H/HeJ mice. Our studies indicate that genetically determined baseline differences in cardiac phenotype have the potential to influence the results of cardiotoxicity studies.

Functional Networks of Nucleocytoplasmic Transport-Related Genes Differentiate Ischemic and Dilated Cardiomyopathies. A New Therapeutic Opportunity

“…RHOJ encodes one of the many small GTP-binding proteins in the Rho family, and was shown to be associated with focal adhesions in endothelial cells [37], [38]. A novel coexpression and integrated pathway network analysis revealed that RHOJ plays a central role in the pathophysiology of murine progressive cardiomyopathy [39]. Thus, RHOJ gene is likely to play a central role in the pathophysiology of DCM.…”

hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling

“…Sample hybridization was performed as previously described [36]. Microarray analysis was performed using Affymetrix Mouse Genome 430 2.0 Array by Microarray core at NIEHS.…”

Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation

“…Previous studies have shown a diversity of cardiac phenotype across distinct mouse strains (3,35) and linked them to gene expression differences (1). Here we have expanded these analyses to look across a larger panel of strains to determine whether these differences can still be attributed to the changes in a single set of genes.…”

“…We expanded the list of fetal genes examined from four to 37 and also tested additional cohorts of genes: regulators of hypertrophic signaling (as determined from knockout and/or transgenesis experiments in mice, n ϭ 142, see Supplemental Table S1 for citations and phenotype information from previous mouse studies), cardiac transcription factors (with known effects on cardiac phenotype, n ϭ 31), and chromatin regulators (see Table 1 for a list of genes in all these groups). 1 Because many of the changes in gene expression (and phenotype) across genetic backgrounds cannot be explained through the actions of SNPs acting in cis (i.e., the variant base is situated in or near the modified gene), we reasoned that alterations in the expression of chromatin modifiers could be a mechanistic explanation for some of these differences in gene expression. To test this, we also included a list of genes for epigenetic and chromatin structural modifiers (referred to as chromatin regulators, n ϭ 124; Table 1) in our analyses.…”

“…Microarray probes for the fetal genes showed significant enrichment for correlations with left atrial mass (enriched 2.97-fold compared with entire transcriptome), change in total heart mass (3.14-fold), and change in LV mass (3.81-fold) after isoproterenol. Individually, considering the seven heart mass and function phenotypes 1 The online version of this article contains supplemental material. Fig.…”