Abstract 203: Sodium Hydrogen Exchanger Isoform Switching And Kchip2 Upregulation In Elderly Porcine Atria
| Autor: | Ritu Kant, Zhaoyang Hu, Jaideep K Malhotra, Trine Krogh-Madsen, David J Christini, Paul M Heerdt, Geoffrey W Abbott |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Circulation Research. 113 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Aging-associated changes in the heart contribute to a wide variety of cardiovascular diseases. The aging atrium becomes increasingly more susceptible to development of atrial fibrillation, and even its pharmacological response to therapeutic drugs alters over time. Changes in structure, function, and pharmacology of the heart can potentially be tied to specific changes in gene expression with aging. Here, seeking molecular correlates of myocardial aging processes, we performed global “whole transcript” analysis of 25,388 genes using 572,667 probes to compare the left atrium (LA) transcriptomes of young adult (9 months old) versus elderly (10 years old) female Sinclair swine. The two genes exhibiting the largest increase in LA expression with aging were NHE2 (9.2-fold; n = 3-4; P = 0.00001) and KCNIP2 (3.8-fold; n = 3-4; P = 0.0002). Real-time qPCR recapitulated the NHE2 results and revealed strongest upregulation with aging in LA, and age-independent expression in the ventricles. NHE2 encodes sodium hydrogen exchanger isoform 2, which was previously considered to not be expressed in mammalian heart, the favored cardiac isoform being NHE1. NHE1 is considered to be important for reperfusion injury after ischemia but, surprisingly, has been a relatively disappointing therapeutic target in clinical trials. Here, we found NHE1 transcript expression in all chambers, but no upregulation in aging heart, raising the possibility that NHE2 upregulation could negatively impact the pharmacological responsiveness of aging tissue to NHE1-specific inhibitors. KCNIP2 encodes potassium channel beta subunit KChIP2, which tightly regulates Ito density. Real-time qPCR indicated equal KCNIP2 upregulation with aging in the LA and RA, and aging-independent expression in the ventricles. In silico modeling predicted the increased KCNIP2 observed here would increase Ito sufficiently to shorten the atrial refractory period, an established substrate for atrial fibrillation. In sum, the findings uncover potential molecular substrates for aging-associated changes in cardiac function, and suggest possible novel therapeutic avenues for aging-related cardiovascular diseases. |
| Databáze: | OpenAIRE |
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