Age is the single biggest risk factor for the developing heart failure and other cardiac problems. With a large increase in the elderly population across Europe, and an associated large increase in elderly patients with chronic cardiac problems, the need to develop our understanding of the ageing process is more pressing than ever. By examining the ageing effect on the ion channel (IC) and transcriptional regulators (TR) expression of the heart, we gleaned novel information regarding the signalling potentially responsible for generating the electrophysiological remodelling with age.
By using a high-throughput quantitative approach, we investigated at a genome-scale the expression of 78 genes encoding IC, transporter subunits and Ca2+-homeostasis molecules in ventricles from embryonic days E15.5, E18.5 and postnatal day 1, day 7, day 20 and adult C57BL6 mice. We have also mapped 158 TR transcripts in the same samples, combined with bioinformatic predictions of sites recognized by the TR and their targets.
Among transcripts involved in electrical signalling and Ca2+-homeostasis, 26/78 exhibited up-regulated expression, while 24 showed down-regulated expression. Using one-way hierarchical clustering analysis, we identified the TRs similarly up- and down-regulated than the ion channel genes. We hypothesized that those clustered IC and TR genes are co-regulated and that they share cisregulatory elements. By in silico investigations, we predicted over-representation of: 1/ Essr⍺ on Nav1.5, Kv2.1, HCN2, RYR2, KChIP2 and Cav⍺2δ1 promoters ; 2/ GATA5 and GATA6 on Cav3.2, Cav1.3, Cav⍺2δ2, NCX1, RIP3-2, Nedd4-2, Cx40 and Cx45 promoters, suggesting that these TRs are involved in the expression of these key ion channel for the cardiac electrical activity. These results were strengthened by inter-species conservation.
Our results provide novel molecular correlates in the ageing heart. The biological validations of these data will give significant potential implications for understanding the mechanisms underlying the fœtal program gene re-expression in cardiac diseases.
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