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

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.

Periostin as a novel biomarker of cardiovascular disease: A systematic evidence landscape of preclinical and clinical studies

“…There are several studies that have suggested that measurement of periostin may be of prognostic value. Such an association has been reported in CAD, HF, MI, and CVDs . In contrast, other study suggested that systemic periostin levels are largely determined by underlying pathogenesis of variety of cancer and allergic diseases, including asthma rather than cardiac function, and that prognostic significance does not remain after adjustment for underlying cardiac function .…”

“…Patients with end‐stage dilated cardiomyopathy who underwent transplantation, with healthy control as a donor group. The periostin expression was upregulated almost fivefold in human failing hearts …”

A novel method for high precision aortic constriction that allows for generation of specific cardiac phenotypes in mice

“…50 These were also tested in mice. [51][52][53] In contrast to suture-based TAC or ORAB, clips do not induce a circular constriction as the aorta is asymmetrically distorted. Since the aorta is compressed rather than constricted, the total crosssectional area at the stenosis is difficult to control.…”

“…Clips adjusted to 27, 30, and 32G needles have been applied without achieving reproducible, graded cardiac remodelling and dysfunction. [51][52][53] We, therefore, believe that the constriction obtained with ORAB is superior to clipconstriction with regards to stenosis standardization.…”

Dysregulation of the Mitochondrial Proteome Occurs in Mice Lacking Adiponectin Receptor 1

“…Protein-protein network analysis and visualizations were performed using Cytoscape (3.7.2). Literature-curated pathway enrichment was achieved using QIAGEN's Ingenuity Pathway Analysis (IPA R , QIAGEN Redwood City, www.qiagen/ingenuity) on differentially expressed proteins using a low-stringency statistical threshold of p < 0.05, followed by Benjamini-Hochberg (BH) post-hoc adjustment, as published previously (24). To perform the enrichment, unfiltered differential expression data of all 3 comparisons were first merged into a single data matrix for uploading to IPA via Uniprot identifier.…”