Dr Charlotte Edling

Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β ( ) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on the molecular mechanisms behind the observed arrhythmic substrate by studying how the expression of selected genes critical for cardiac function differs in wild-type (WT) compared with knockout mice and young compared with aged mice. We found that a clear majority of genes are down-regulated in the ventricular tissue compared with the WT. Although most individual genes are not significantly differentially expressed, a pattern is apparent when the genes are grouped according to their functional properties. Genes encoding proteins relating to ATPase activity, potassium ion channels relating to repolarisation and resting membrane potential, and genes encoding proteins in the cAMP pathway are found to be significantly down-regulated in the deficient mice. On the contrary, the pacemaker channel genes and are up-regulated in subsets of the deficient tissue. Furthermore, we found that with age, especially in the genotype, most genes are up-regulated including genes relating to the resting membrane potential, calcium homeostasis, the cAMP pathway, and most of the tested adrenoceptors. In conclusion, we here demonstrate how a complex pattern of many modest changes at gene level may explain major functional differences of the action potential related to ageing and mitochondrial dysfunction.

Increases in the prevalence of obesity, insulin resistance, and metabolic syndrome has led to the increase of atrial fibrillation (AF) cases in the developed world. These AF risk factors are associated with mitochondrial dysfunction, previously modelled using peroxisome proliferator activated receptor- (PPAR) coactivator-1 (Pgc-1)-deficient murine cardiac models. We explored gene and protein expression profiles of selected molecular targets related to electrophysiological function in murine Pgc-1(-/-) atria. qPCR analysis surveyed genes related to Na+-K+-ATPase, K+ conductance, hyperpolarisation-activated cyclic nucleotide-gated (Hcn), Na+ channels, Ca2+ channels, and indicators for adrenergic and cholinergic receptor modulation. Western blot analysis for molecular targets specific to conduction velocity (Na(v)1.5 channel and gap junctions) was performed. Transcription profiles revealed downregulation of molecules related to Na+-K+-ATPase transport, Hcn-dependent pacemaker function, Na+ channel-dependent action potential activation and propagation, Ca2+ current generation, calsequestrin-2 dependent Ca2+ homeostasis, and adrenergic (1D) dependent protection from hypertrophic change. Na(v)1.5 channel protein expression but not gap junction expression was reduced in Pgc-1(-/-) atria compared to WT. Na(v)1.5 reduction reflects corresponding reduction in its gene expression profile. These changes, as well as the underlying Pgc-1(-/-) alteration, suggest potential pharmacological targets directed towards either upstream PGC-1 signalling mechanisms or downstream ion channel changes.

Introduction: Ageing and chronic metabolic disorders are associated with mitochondrial dysfunction and cardiac pro-arrhythmic phenotypes which were recently attributed to slowed atrial and ventricular action potential (AP) conduction in peroxisome proliferator-activated receptor gamma co-activator deficient (Pgc-1 beta(-/-)) mice. Methods: We compared expression levels of voltage-gated Na channel (Na(V)1.5) and gap junction channels, Connexins 40 and 43 (Cx40 and Cx43) in the hearts of young and old, and wild-type (WT) and Pgc-beta(-/-) mice. This employed Western blotting (WB) for Na(V)1.5, Cx40 and Cx43 in atrial/ventricular tissue lysates, and immunofluorescence (IF) from Cx43 was explored in tissue sections. Results were analysed using two-way analysis of variance (ANOVA) for independent/interacting effects of age and genotype. Results: In atria, increased age and Pgc-1 beta(-/-) genotype each independently decreased both Cx40 and Cx43 expression without interacting effects. In IF experiments, both age and Pgc-1 beta deletion independently reduced Cx43 expression. In ventricles, age and genotype exerted interacting effects in WB studies of Na(V)1.5 expression. Young Pgc1 beta(-/-) then showed greater Na(V)1.5 expression than young VVT ventricles. However, neither age nor Pgc-beta(-/-) deletion affected Cx43 expression, independently or through interacting effects in both WB and IF studies. Conclusion: Similar pro-arrhythmic atrial/ventricular phenotypes arise in aged/Pgc-beta(-/-) from differing contributions of altered protein expression and functional effects that may arise from multiple acute mechanisms.

BackgroundAlpha-synuclein is associated with neurodegeneration in Parkinson's disease (PD). Recent studies have increasingly recognized incidences of cardiac complaints in PD patients. In particular, the occurrence of arrhythmias in PD patients may indicate potential electrophysiological alterations in the heart. Alpha-synuclein aggregates have been known to have disruptive effects on cell membranes. However, the effect of alpha-synuclein on the heart and sympathetic neuronal tissues remains unknown.ObjectiveThis study investigated the electrophysiological effects of alpha-synuclein aggregates in myocardium and cardiac sympathetic nervous system, potentially reflecting cardiac electrophysiological alteration in PD.MethodsWe measured the sodium and potassium currents from murine ventricular myocardium and stellate ganglia using the loose patch clamp technique. The tissues were exposed to bioactive alpha-synuclein aggregates, and currents were measured under three different conditions: baseline, alpha-synuclein treatment, and wash out.ResultsThe experiments showed that alpha-synuclein aggregates altered the maximum cardiac sodium current ( ) (ANOVA, p 

Raw data from mass spectrometry on decellularised and deglycosylated murine atrial tissue. Data includes #PSM, #peptides and abundance values, amongst other variables.

The cardiac atrial extracellular matrix (ECM) is central to age-associated cardiac remodeling and subsequent decline in cardiac functioning. Despite this, the composition of the atrial ECM and how it changes with age is not yet known. This study utilized mass spectrometry to evaluate the composition of murine atria in young (12 weeks) and old (77 weeks) C57BL/6J mice. The tissue was decellularized, ECM and ECM-associated proteins were extracted with GuHCl, and proteins were deglycosylated to enable identification of glycosylated peptides. Two hundred and thirty-seven ECM and ECM-associated proteins were found to be significantly differentially expressed with age. Some proteins (MMP9, S100A9, VWA3A, CTSD, CCL8) were more than threefold increased with age, proteoglycans were modestly decreased, while the overall collagen content was markedly decreased. STRING network mapping of physical associations predicted that both PLOD3 and PDGFA interact with the collagens that decreased with age. The results suggest that the mechanism behind age-associated atrial stiffness is not due to an increase in collagen content as previously believed, but an increase in cross-linking, potentially facilitated by PLOD3. Additionally, several of the significant proteins have not previously been associated with cardiac aging and thus are potential drug targets for age-associated cardiac fibrosis and other age-associated conditions.

The cardiac extracellular matrix (ECM) is involved in several pathological conditions, and age itself is also associated with certain changes in the heart: it gets larger and stiffer, and it develops an increased risk of abnormal intrinsic rhythm. This, therefore, makes conditions such as atrial arrythmia more common. Many of these changes are directly related to the ECM, yet the proteomic composition of the ECM and how it changes with age is not fully resolved. The limited research progress in this field is mainly due to the intrinsic challenges in unravelling tightly bound cardiac proteomic components and also the time-consuming and costly dependency on animal models. This review aims to give an overview of the composition of the cardiac ECM, how different components aid the function of the healthy heart, how the ECM is remodelled and how it is affected by ageing.

Coronary artery disease (CAD) is the leading cause of sudden cardiac death in adults, and new methods of predicting disease and risk-stratifying patients will help guide intervention in order to reduce this burden. Current CAD detection involves multiple modalities, but the consideration of other biomarkers will help improve reliability. The aim of this narrative review is to help researchers and clinicians appreciate the growing relevance of miRNA in CAD and its potential as a biomarker, and also to suggest useful miRNA that may be targets for future study. We sourced information from several databases, namely PubMed, Scopus, and Google Scholar, when collating evidentiary information. MicroRNAs (miRNA) are short, noncoding RNAs that are relevant in cardiovascular physiology and pathophysiology, playing roles in cardiac hypertrophy, maintenance of vascular tone, and responses to vascular injury. CAD is associated with changes in miRNA expression profiles, and so are its risk factors, such as abnormal lipid metabolism and inflammation. Thus, they may potentially be biomarkers of CAD. Nevertheless, there are limitations in using miRNA. These include cost and the presence of several confounding factors that may affect miRNA profiles. Furthermore, there is difficulty in the normalisation of miRNA values between published studies, due to pre-analytical variations in samples.