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

Abstract

.-Myocardial aging leads to a reduction of ␤-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 ␤1-adrenergic receptor and adenylyl cyclase mRNAs, whereas the mRNA encoding ␤-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 ␤3, 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 THE ABILITY OF THE HEART to respond to excitatory signaling cues is the dominant regulator of cardiac function. The hallmark of the aged heart is an impairment of the excitatory response to ␤-adrenergic agonists leading to a deficit in cardiac contractility and metabolism (26,27). The ␤-adrenergic signaling system also plays a central role in the pathophysiology of congestive heart failure (17). Despite the importance of this system, the factors that contribute to a decreased responsiveness in signaling, particularly with aging, are unclear.The ␤-adrenergic signaling cascade is composed of membrane receptors, signal transducers, and downstream effector molecules. The receptor-signaling cascade is dynamically regulated by the phosphorylation state catalyzed by common and pathway-specific enzymes. Although the individual candidate approach has provided some clues as to the changes that occur with aging, the basic premise guiding these studies is that the determinants of ␤-adrenergic responsiveness will be few and the regulatory circuits will be simple. However, it is clear that the signaling pathways for membrane receptors are not simple but are highly integrated a...

Adenosine-mediated cardioprotection in the aging myocardium

“…Several studies support impaired adenosine responses in aged heart [59][60][61][62]64,[71][72][73], though findings regarding AR expression/signaling vary [16,60,71]. Our recent data verifies failure in adenosinergic protection with even moderate aging in mouse [16], consistent with findings of Gao et al [64] and Schulman et al [65] in aged rat hearts.…”

“…Despite no change in baseline A 1 AR expression in rat [60] and mouse [16], age-related changes in Adora1 mRNA are observed, though findings vary. Arosio et al [88] and Dobson et al [73] observed elevations in Adora1 whereas Jenner et al [89] reported a 5-fold reduction in Adora1 with age. Irrespective of effects of age on mRNA, it appears that changes do not translate into altered A 1 AR expression [16,60].…”

Alterations of epinephrine-induced gluconeogenesis in aging

“…β 2 -AR desensitization related GRK activity and expression of GRK2, GRK3, but not GRK5 and β-arrestin, increase as an organism ages (Schutzer et al, 2001). In addition, the gene expression profiles for aged myocardial tissues showed a reduction in β 2 -AR-induced metabolic and contractile responsiveness, and an increase in β-arrestin mRNA expression (Dobson et al, 2003). Our results also show that GRK3 and β-arrestin desensitization systems are associated with decreased epinephrine-induced gluconeogenesis.…”

“…Electric shock induced catecholamine secretion from the adrenal medulla together with decreased blood glucose responses in old rats (Mabry et al, 1995). Catecholamine-stimulated lipolysis, glycogenolysis, and β 2 -AR mediated vasorelaxation all declined in aged animal aortic tissues (Dax et al, 1981;Fraeyman and van Ermen, 1993;Dobson et al, 2003). To understand the reasons for the reduced response to β 2 -AR-stimulated intracellular function, aged rat hepatocyte viability, receptor density, receptor binding affinity, and adenylate cyclase activities were studied (Morgan et al, 1983;Fraeyman et al, 2000).…”

Age-related changes in cardiac structure and function in Fischer 344 × Brown Norway hybrid rats

“…Snyder et al (44) identified a decrease in the release of norepinephrine, which may affect blood pressure and %FS. Indeed, others also have shown a reduced response to catecholamines in aged aortas and hearts (5,19,25,38,44). Arosio et al (5) also have reported an increase in adenosine A 1 receptor gene expression in the aging rat heart, which would have a similar antiadrenergic effect.…”