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Molecular mechanisms of reduced ß-adrenergic signaling in the aged heart as revealed by genomic profiling

¹ Genomic Physiology Group, Department of Physiology, University of Massachusetts Medical School, Worcester 01655
² Laboratory of Genetic Physiology, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115

Myocardial aging leads to a reduction of ß-adrenergic receptor-induced metabolic and contractile responsiveness. We hypothesize that a change in the patterns of gene expression is important in these age-related events. To test this, hearts were harvested from young and aged male rats (3–4 and 20–22 mo, respectively). Total mRNA was extracted and prepared for hybridization to Affymetrix U34A GeneChips. Filtering criteria, involving fold change and a statistical significance cutoff were employed, yielding 263 probe pairs exhibiting differential signals. Of the 163 annotated genes, at least 56 (34%) were classified as signaling/cell communication. Of these 56, approximately half were directly involved in G protein-coupled receptor signaling pathways. We next determined which of these changes might be involved in anti-adrenergic activity and identified 19 potentially important gene products. Importantly, we observed a decrease in ß₁-adrenergic receptor and adenylyl cyclase mRNAs, whereas the mRNA encoding ß-arrestin increased. Furthermore, the results demonstrate an increase in mRNAs encoding the adenosine A₁ receptor and phospholipase D, which could increase anti-adrenergic effects. Moreover, the mRNAs encoding the muscarinic M3 receptor, nicotinic acetylcholine receptor ß3, and nicotinic acetylcholine receptor-related protein were increased as was the mRNA encoding guanylate kinase-associated protein. Interestingly, we also observed eight mRNAs whose abundance changed three- to sixfold with aging that could be considered as being compensatory. Although these results do not prove causality, they demonstrate that cardiac aging is associated with changes in the profiles of gene expression and that many of these changes may contribute to reduced adrenergic signaling.

gene expression; aging; anti-adrenergic; G protein-coupled receptors; physiological genomics

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