Abstract 21111: Adaptive and Pathologic Hypertrophy Exhibit Distinct and Separate Gene Expression Profiles: Comprehensive Analysis and Validation of Cardiac Hypertrophy Microarray Datasets in Public Domain
Introduction: Cardiac hypertrophy can be pathological or adaptive. Although structurally and functionally distinguishable, the molecular bases of this distinction are less well defined. Deducing processes involved in each may present novel means to block heart failure while potentially enhancing the adaptive process.
Objectives: To use known public domain microarray datasets to determine genes and pathways that characterize adaptive and pathological hypertrophy, followed by validation in mouse models of exercise and heart failure.
Methods: Microarray datasets were obtained from NCBI GEO. Fold changes and p-values were determined for each gene, and pathway analyses performed on each dataset. For the validation study, 9 wk exercise and 6 wk TAC model were developed in mouse to represent adaptive and pathological hypertrophy, respectively.
Results: We obtained theoretical gene expression profiles that distinguish pathological and adaptive hypertrophy. Animal models of pathological hypertrophy show significant upregulation of genes associated with inflammation, extracellular matrix development, NFAT and apoptotic-related pathways, coupled with downregulation of mitochondrial genes. At early time points, downregulation of beta adrenergic genes occurs alongside the upregulation of anti-apoptotic genes, indicating compensatory mechanisms. In contrast, adaptive hypertrophy models present increase in metabolic and PI3K pathway genes along with decrease in inflammation and the Gi/Gs pathway genes. Some pathways are enriched with both hypertrophies, but only in the opposing direction. Overall, each hypertrophy exhibits a unique gene and pathway profile suggesting that distinct mechanisms drive these two separate events. The signatures identified by data mining were then validated in mouse models of adaptive and pathological hypertrophy.
Conclusions: Comparing microarray datasets across models of pathological and adaptive hypertrophy, we obtained gene expression profiles that are unique to each, including common processes that change in the opposite direction. We validated this analysis in in vivo models of hypertrophy. The findings will aid in the identification of novel targets for therapeutic intervention in heart failure.
- © 2010 by American Heart Association, Inc.