ABSTRACT
[Figure: see text].
Subject(s)
Coronary Artery Disease/genetics , Genetic Variation , Scavenger Receptors, Class B/genetics , Adult , Age of Onset , Animals , Coronary Artery Disease/diagnosis , Coronary Artery Disease/epidemiology , Female , Genetic Association Studies , Genetic Predisposition to Disease , HEK293 Cells , Hep G2 Cells , Hepatocytes/metabolism , Heredity , Heterozygote , Humans , Induced Pluripotent Stem Cells/metabolism , Male , Mice, Inbred C57BL , Middle Aged , Pedigree , Phenotype , Risk Assessment , Risk Factors , Scavenger Receptors, Class B/metabolism , Severity of Illness Index , Exome SequencingABSTRACT
Spectrins are cytoskeletal proteins essential for membrane biogenesis and regulation and serve critical roles in protein targeting and cellular signaling. αII spectrin (SPTAN1) is one of two α spectrin genes and αII spectrin dysfunction is linked to alterations in axon initial segment formation, cortical lamination, and neuronal excitability. Furthermore, human αII spectrin loss-of-function variants cause neurological disease. As global αII spectrin knockout mice are embryonic lethal, the in vivo roles of αII spectrin in adult heart are unknown and untested. Here, based on pronounced alterations in αII spectrin regulation in human heart failure we tested the in vivo roles of αII spectrin in the vertebrate heart. We created a mouse model of cardiomyocyte-selective αII spectrin-deficiency (cKO) and used this model to define the roles of αII spectrin in cardiac function. αII spectrin cKO mice displayed significant structural, cellular, and electrical phenotypes that resulted in accelerated structural remodeling, fibrosis, arrhythmia, and mortality in response to stress. At the molecular level, we demonstrate that αII spectrin plays a nodal role for global cardiac spectrin regulation, as αII spectrin cKO hearts exhibited remodeling of αI spectrin and altered ß-spectrin expression and localization. At the cellular level, αII spectrin deficiency resulted in altered expression, targeting, and regulation of cardiac ion channels NaV1.5 and KV4.3. In summary, our findings define critical and unexpected roles for the multifunctional αII spectrin protein in the heart. Furthermore, our work provides a new in vivo animal model to study the roles of αII spectrin in the cardiomyocyte.
Subject(s)
Arrhythmias, Cardiac/pathology , Disease Models, Animal , Heart Failure/pathology , Ischemia/pathology , Myocytes, Cardiac/pathology , Spectrin/physiology , Animals , Arrhythmias, Cardiac/etiology , Cells, Cultured , Female , Heart Failure/etiology , Humans , Ischemia/etiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , PhenotypeABSTRACT
AIMS: Right ventricular failure (RVF) varies significantly from the more common left ventricular failure (LVF). This study was undertaken to determine potential molecular pathways that are important in human right ventricular (RV) function and may mediate RVF. MATERIALS AND METHODS: We analyzed mRNA of human non-failing LV and RV samples and RVF samples from patients with pulmonary arterial hypertension (PAH), and post-LVAD implantation. We then performed transcript analysis to determine differential expression of genes in the human heart samples. Immunoblot quantification was performed followed by analysis of non-failing and failing phenotypes. KEY FINDINGS: Inflammatory pathways were more commonly dysregulated in RV tissue (both non-failing and failing phenotypes). In non-failing human RV tissue we found important differences in expression of FIGF, TRAPPAC, and CTGF suggesting that regulation of normal RV and LV function are not the same. In failing RV tissue, FBN2, CTGF, SMOC2, and TRAPP6AC were differentially expressed, and are potential targets for further study. SIGNIFICANCE: This work provides some of the first analyses of the molecular heterogeneity between human RV and LV tissue, as well as key differences in human disease (RVF secondary to pulmonary hypertension and LVAD mediated RVF). Our transcriptional data indicated that inflammatory pathways may be more important in RV tissue, and changes in FIGF and CTGF supported this hypothesis. In PAH RV failure samples, upregulation of FBN2 and CTGF further reinforced the potential significance that altered remodeling and inflammation play in normal RV function and failure.
