generation-organ-conditioned-media-applications-for-studying-organ

Generation of Organ-conditioned Media and Applications for Studying Organ-specific Influences on Breast Cancer Metastatic Behavior

Breast cancer preferentially metastasizes to the lymph node, bone, lung, brain and liver in breast cancer patients. Previous research efforts have focused ...

viral-transgene-expression-rodent-hearts-assessment-cardiac

Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk

Heart disease is the leading cause of morbidity and mortality worldwide. Due to the ease of handling&#160;and abundance of transgenic strains, rodents ...

London Health Sciences Centre

University of Ottawa Heart Institute

University of Ottawa

Wnt/β-catenin signaling is activated in the heart after myocardial infarction (MI). This study aims to investigate if β-catenin deletion affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific β-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at 8 weeks after MI, associated with reduced scar size and attenuated chamber dilation. qPCR analyses of both myocardial tissues and purified cardiomyocytes demonstrated upregulation of Wnt pathway genes in border and infarct regions after MI, including Wnt ligands (such as Wnt4) and receptors (such as Fzd1 and Fzd2). At 1 week after MI, cardiac sodium channel gene (Scn5a) transcript was reduced in WT but not in KO hearts, consistent with previous studies showing Scn5a inhibition by Wnt/β-catenin signaling. At 8 weeks after MI when Wnt genes have declined, Scn5a returned to near sham levels and K channel gene downregulations were not different between WT and KO mice. This study demonstrated that VT susceptibility in the chronic phase after MI is reduced in mice with cardiomyocyte-specific β-catenin deletion primarily through attenuated structural remodeling, but not ion channel gene alterations.

Cardiomyocyte-specific deletion of β-catenin protects mouse hearts from ventricular arrhythmias after myocardial infarction.

Previous studies have established that transmural gradients of the fast transient outward K current () correlate with regional differences in action potential (AP) profile and excitation-contraction coupling (ECC) with high  expression in the epimyocardium (EPI) being associated with short APs and low contractility and vice versa. Herein, we investigated the effects of altering the  gradients on transmural contractile properties using mice lacking  (Irx5-KO) or lacking  (K4.2-KO) or both. Irx5-KO mice exhibited decreased global LV contractility in association with elevated , as well as reduced cell shortening and Ca transient amplitudes in cardiomyocytes isolated from the endomyocardium (ENDO) but not in cardiomyocytes from the EPI. Transcriptional profiling revealed that the primary effect of  ablation on ECC-related genes was to increase  gene expression (i.e.,  and ) in the ENDO, but not the EPI. By contrast, K4.2-KO mice showed selective increases in cell shortening and Ca transients in isolated EPI cardiomyocytes, leading to enhanced ventricular contractility and mice lacking both  and  displayed elevated ventricular contractility, comparable to K4.2-KO mice, demonstrating a dominant role of -dependent modulation of  in the regulation of contractility. Our findings show that the transmural electromechanical heterogeneities in the healthy ventricles depend on the -dependent  gradients. These observations provide a useful framework for assessing the molecular mechanisms underlying the alterations in contractile heterogeneity seen in the diseased heart. Irx5 is a vital transcription factor that establishes the transmural heterogeneity of ventricular myocyte contractility, thereby ensuring proper contractile function in the healthy heart. Regional differences in excitation-contraction coupling in the ventricular myocardium are primarily mediated through the inverse relationship between Irx5 and the fast transient outward K current () across the ventricular wall.

Ying Xia

London Regional Cancer Program

London Health Sciences Centre

Generation of Organ-conditioned Media and Applications for Studying Organ-specific Influences on Breast Cancer Metastatic Behavior

Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk