17 Changes in the Role of the SR in SAN Function Across the Lifespan May Be responsible for Changing Pacemaker Stability and Response

Abstract

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...