Reciprocal transcriptional regulation of metabolic and signaling pathways correlates with disease severity in heart failure

Andreas S. Barth, Ami Kumordzie, Constantine Frangakis, Kenneth B. Margulies, Thomas P. Cappola, Gordon F. Tomaselli

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background-Systolic heart failure (HF) is a complex systemic syndrome that can result from a wide variety of clinical conditions and gene mutations. Despite phenotypic similarities, characterized by ventricular dilatation and reduced contractility, the extent of common and divergent gene expression between different forms of HF remains a matter of intense debate. Methods and Results-Using a meta-analysis of 28 experimental (mouse, rat, dog) and human HF microarray studies, we demonstrate that gene expression changes are characterized by a coordinated and reciprocal regulation of major metabolic and signaling pathways. In response to a wide variety of stressors in animal models of HF, including ischemia, pressure overload, tachypacing, chronic isoproterenol infusion, Chagas disease, and transgenic mouse models, major metabolic pathways are invariably downregulated, whereas cell signaling pathways are upregulated. In contrast to this uniform transcriptional pattern that recapitulates a fetal gene expression program in experimental animal models of HF, human HF microarray studies displayed a greater heterogeneity, with some studies even showing upregulation of metabolic and downregulation of signaling pathways in end-stage human hearts. These discrepant results between animal and human studies are due to a number of factors, prominently cardiac disease and variable exposure to cold cardioplegic solution in nonfailing human samples, which can downregulate transcripts involved in oxidative phosphorylation (OXPHOS), thus mimicking gene expression patterns observed in failing samples. Additionally, β-blockers and ACE inhibitor use in end-stage human HF was associated with higher levels of myocardial OXPHOS transcripts, thus partially reversing the fetal gene expression pattern. In human failing samples, downregulation of metabolism was associated with hemodynamic markers of disease severity. Conclusions- Irrespective of the etiology, gene expression in failing myocardium is characterized by downregulation of metabolic transcripts and concomitant upregulation of cell signaling pathways. Gene expression changes along this metabolic-signaling axis in mammalian myocardium are a consistent feature in the heterogeneous transcriptional response observed in phenotypically similar models of HF.

Original languageEnglish (US)
Pages (from-to)475-483
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume4
Issue number5
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

Fingerprint

Metabolic Networks and Pathways
Heart Failure
Gene Expression
Down-Regulation
Oxidative Phosphorylation
Myocardium
Up-Regulation
Animal Models
Cardioplegic Solutions
Systolic Heart Failure
Chagas Disease
Isoproterenol
Angiotensin-Converting Enzyme Inhibitors
Transgenic Mice
Meta-Analysis
Dilatation
Heart Diseases
Ischemia
Hemodynamics
Dogs

Keywords

  • Fetal gene program
  • Heart failure
  • Oxidative phosphorylation

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

Reciprocal transcriptional regulation of metabolic and signaling pathways correlates with disease severity in heart failure. / Barth, Andreas S.; Kumordzie, Ami; Frangakis, Constantine; Margulies, Kenneth B.; Cappola, Thomas P.; Tomaselli, Gordon F.

In: Circulation: Cardiovascular Genetics, Vol. 4, No. 5, 01.10.2011, p. 475-483.

Research output: Contribution to journalArticle

Barth, Andreas S. ; Kumordzie, Ami ; Frangakis, Constantine ; Margulies, Kenneth B. ; Cappola, Thomas P. ; Tomaselli, Gordon F. / Reciprocal transcriptional regulation of metabolic and signaling pathways correlates with disease severity in heart failure. In: Circulation: Cardiovascular Genetics. 2011 ; Vol. 4, No. 5. pp. 475-483.
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