Ageing‐related changes of connexins and conduction within the sinoatrial node

Abstract

Clinical studies have shown that sinoatrial node dysfunction occurs at the highest incidence in the elderly population. Guinea-pigs were studied throughout their lifespan (i.e. birth to 38 months) to investigate the possible mechanism leading to nodal dysfunction. Using immunofluorescence with confocal microscopy, Cx43 protein expression was shown at birth to be present throughout the sinoatrial node and atrial muscle, however, at one month Cx43 protein was not expressed in the centre of the sinoatrial node. Throughout the remainder of the animal's lifespan the area of tissue lacking Cx43 protein progressively increased. Western blot provided verification by quantitative analysis that Cx43 protein expression within the sinoatrial node decreased with age; however, the expression of other cardiac connexins, Cx40 and Cx45, did not differ with age. Analysis of conduction maps showing propagation of the action potential across the sinoatrial node, from the initiation point to the crista terminalis, found that the action potential conduction time taken and conduction distance increased proportionally with age; conversely the conduction velocity decreased with age. We have shown ageing induces degenerative changes in action potential conduction, contributed to by the observed loss of Cx43 protein. Our data identify Cx43 as a potential therapeutic target for quashing the age-related deterioration of the cardiac pacemaker.

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

“…Statuto et al (22) reported a progressive decrease of the expression of Cx43 and GJIC in replicative senescence of cultured HEL-299 fibroblasts and termed Cx43 as a biomarker of cell senescence. It also has been shown that the expression and function of Cx43 in astrocytic cells and aortic endothelium were age related, suggesting that Cx43 and GJIC may play a role in the process of cell aging (23)(24)(25)(26).…”

Fibrosis, Electrics and Genetics

“…Decreased expression of Cx43 in the vicinity of the SAN may account for the observed increase in SAN conduction time and SAN exit block seen with aging. 44 It has also been noted in the guinea-pig that Ca + channel expression (Cav1.2) expression declines in the SAN during aging. 23 …”

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

“…Fibrotic change could directly disrupt gap junction function, increasing tissue resistance,35 or increase fibroblast‐cardiomyocyte coupling, increasing effective membrane capacitance 36. More recent studies indeed implicate abnormal gap junction function in both SAN and AVN disease 37, 38. Interestingly, oxidative stress, associated with mitochondrial impairment increases transforming growth factor (TGF)‐β activity,39 in turn implicated in such age‐related myocardial fibrosis 40.…”