Aging is an inevitable time-dependent progression associated with a functional decline of the cardiovascular system even in 'healthy' individuals. Age positively correlates with an increasing risk of cardiac problems including arrhythmias. Not only the prevalence but also the severity of arrhythmias escalates with age. The reasons for this are multifactorial but dysregulation of intracellular calcium within the heart is likely to play a key role in initiating and perpetuating these life-threatening events. We now know that several aspects of cardiac calcium regulation significantly change with advancing age - changes that could produce electrical instability. Further development of knowledge of the mechanisms underlying these changes will allow us to reduce what currently is an inevitable increase in the incidence of arrhythmias in the elderly.
Cardiac arrhythmias are associated with raised intracellular [Ca2+] and slowed action potential conduction caused by reduced gap junction (GJ) electrical conductance (Gj). Ventricular GJs are composed of connexin proteins (Cx43), with Gj determined by Cx43 phosphorylation status. Connexin phosphorylation is an interplay between protein kinases and phosphatases but the precise pathways are unknown. We aimed to identify key Ca2+-dependent phosphorylation sites on Cx43 that regulate cardiac gap junction conductance and action potential conduction velocity. We investigated the role of the Ca2+-dependent phosphatase, calcineurin. Intracellular [Ca2+] was raised in guinea-pig myocardium by a low-Na solution or increased stimulation. Conduction velocity and Gj were measured in multicellular strips. Phosphorylation of Cx43 serine residues (S365 and S368) and of the intermediary regulator I1 at threonine35 was measured by Western blot. Measurements were made in the presence and absence of inhibitors to calcineurin, I1 or protein phosphatase-1 and phosphatase-2.Raised [Ca2 +]i decreased Gj, reduced Cx43 phosphorylation at S365 and increased it at S368; these changes were reversed by calcineurin inhibitors. Cx43-S368 phosphorylation was reversed by the protein kinase C inhibitor chelerythrine. Raised [Ca2+]i also decreased I1 phosphorylation, also prevented by calcineurin inhibitors, to increase activity of the Ca2+-independent phosphatase, PPI. The PP1 inhibitor, tautomycin, prevented Cx43-365 dephosphorylation, Cx43-S368 phosphorylation and Gj reduction in raised [Ca2+]i. PP2A had no role. Conduction velocity was reduced by raised [Ca2+]i and reversed by calcineurin inhibitors. Reduced action potential conduction and Gj in raised [Ca2+] are regulated by calcineurin-dependent Cx43-S365 phosphorylation, leading to Cx43-S368 dephosphorylation. The calcineurin action is indirect, via I1 dephosphorylation and subsequent activation of PP1.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-016-1885-7) contains supplementary material, which is available to authorized users.
Background We aimed to identify differentially expressed genes (DE) in whole blood following myocardial infarction (MI) or unstable angina (UA), and assess these functionally in zebrafish models. Methods We performed whole blood microarrays comparing the transcriptome of patients with MI with UA at serial timepoints post-admission. We then examined the effect of knocking down one DE gene (KIAA1109) by morpholino antisense and examining the effect on vascular development in zebrafish embryos. Results KIAA1109, a gene of completely unknown function was significantly down regulated in MI compared with UA 1d post MI, with no difference at later timepoints. Knockdown of KIAA1109 in developing zebrafish showed KIAA1109 morphants developed normally but developed cerebral haemorrhage (control 10% vs 50% morphants p<0.05). Haemorrhage volume was greater in KIAA1109 morphants (control 1.2µm 3 vs morphants 11.3µm 3 p<0.05). KIAA1109 knockdown decreased endothelial cell (EC) number in the forebrain (control 73±6 vs 47±4 morphants) and hindbrain (control 95±7 vs 53±4 morphants). Incubation with the VEGF inducer GS4012 completely rescued the hemorrhagic phenotype.We performed a microarray comparing whole embryo RNA from KIAA1109 morphants with control to assess the transcriptional effect of loss of function of KIAA1109. This identified DE genes that were significantly down regulated such as genes involved in the cadherin-signalling pathway and genes involved in the NOTCH pathway. Conclusion KIAA1109 is down regulated in peripheral blood early after MI. KIAA1109 knockdown induced cerebral bleeding in zebrafish embryos that is rescued by VEGF induction, suggesting KIAA1109 is required for vascular integrity. Old age has been recognised to be a major risk factor for the development of cardiovascular disease and growing evidence suggests a role for oxidative stress. However, it remains unclear if cardiovascular oxidative stress is associated with ageing-related insulin resistance and metabolic disorders. In this study, we investigated the relationship between metabolic changes and cardiovascular oxidative stress using C57BL/6 mice at young (3-4m) and old (22-24 m) ages. There was no significant difference in the food and water intake between young and aged mice. However, there was a significant increase in bodyweight (24.97±0.75g at 3-4m, 39.34±2.56g at 20m) and the epididymal fat pad weight (0.42±0.03g at 3-4m vs 1.32±0.21g at 22-24m) in ageing mice. Increased body fat deposition in the ageing mice was accompanied with a significant decrease (40%) in fasting serum triglyceride levels, a significant increase in fasting insulin levels (0.69±0.24µg/L at 3-4m, 2.08±0.46µg/L at 21-24m), and impaired glucose tolerance as evidenced by a significantly delayed clearance of glucose (P<0.05). These ageing-related metabolic disorders were accompanied with significant increases in 14 15 superoxide production in aortas and hearts of ageing mice as compared to their young controls. In conclusion, the normal ageing process causes cardiovascular...
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Welcome to the Winter 2014 edition of Physiology News Introduction 05 Editorial News in brief 06 #Biobakes LifeSci TRC 07 Student-led 'Physiology Challenge' for Biology Week at the University of Leeds Physiology Feed 08 Policy Focus In depth 10 Cambridge physiology scores a century 12 Physiology on the go 14 A tribute to Bernhard Frankenhaeuser 1915-1994 Meetings & events 16 Forthcoming events Meeting notes: Obesity -a physiological perspective 17 Meeting notes: Special symposium for Dr Robert Banks 18 Young Life Scientists' Symposium 2014 19 Meeting notes: International lecture 2014 20 We know where we are going but how do we get there? FeaturesHuman metabolism and obesity: the influence of exercise Exercise: more than just a role in energy balanceSleep disturbance alters autonomic balance to the heartThe mighty protein: Insulin-like growth factor type 1
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