Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504719
Title: Age-dependent remodelling of thesinoatrial node and right atrium
Author: Gerges, Joseph Fouad Yanni
Awarding Body: The University of Manchester
Current Institution: University of Manchester
Date of Award: 2008
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Abstract:
Ageing is associated with a decline in the function of the sinoatrial node (SAN; e.g. there is decrease in intrinsic heart rate) and an increase in the incidence of sick sinus syndrome. We investigated the effect of ageing on ion channels (HCN4 responsible for If and Navl.l and Navl.5 responsible for INa) in the SAN using young and old (3 and 24 months of age) Wistar-Hanover rats. Extracellular potentials recorded from isolated SAN/atrial preparations showed that, in the older rats, the leading pacemaker site was located more towards the inferior vena cava (l±0.3 mm from junction of superior vena cava with atrium in young and 2A±OA mm in old) and the spontaneous cycle length (CL) was greater by 24 % (i.e. intrinsic 'heart rate' was 20 % slower). The effect of blockers of HCN4, Nav1.l and Nav1.5 on these preparations was examined. In other preparations, HCN4, HCNl, Nav1.l and Nav1.5 mRNA and protein was measured using quantitative PCR and immunohistochemistry. Block ofHCN4 by 2 roM Cs+ caused a significantly greater increase in CL in old rats (22 % in young and 45 % in old). HCN4 (mRNA and protein) was expressed in the SAN (but not in atrium). There was no age-dependent change in its density, but the volume of HCN4-positive tissue was 97 % greater in old rats. Block of Nav1.l by 100 nM TTX caused an increase in CL (5±2 %) in young, but a decrease (9±3 %) in old, rats. Nav1.l (mRNA) was expressed in the SAN (and atrium), and there was an age-dependent decrease in its density in the SAN (by 44 %). Block of Nav1.5 by the subsequent addition of 2 J.1M TTX caused a significantly greater increase in CL in old rats (11 % in young and 37 % in old). Nav1.5 (protein) was expressed in the atrium, but not in the SAN, and the volume of Navl.5-negative tissue was 97 % greater in old rats. Although it is well known that there is an age-dependent remodelling of the extracellular matrix (ECM) in the heart, it is unclear whether there is a remodelling of ECM in the SAN. The aim of the present study was to investigate (using quantitative PCR) the effect of age on the expression of components of the ECM and factors that control the ECM in the SAN. With age, at the mRNA level, there was a statistically significant increase in transforming growth factor ~l and tumour necrosis factor a and a significant decrease in elastin and collagen types I and IlIa. In addition, Picro Sirius red staining showed that in the SAN there is a significant decrease in the total content of collagen at the protein level with age. The expression of matrix metalloproteinase 2 mRNA, responsible for collagen degradation, underwent a significant decrease in the SAN with age. On the other hand, the expression of fibronectin and vimentin mRNA did not change in the SAN with age. Furthermore, the expression of integrins (aI, a5 and ~l) at the mRNA level did not change in the SAN with age. Integrins are a family ofmembrane receptors that playa role in the mediation of cell interactions. It is concluded that, although there is a remodelling of the ECM, the decline in SAN function during ageing is likely to be the result of a remodelling of ion channel expression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Not available Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.504719  DOI: Not available
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