Cardiac chamber formation represents an essential evolutionary milestone that allows for the heart to receive (atrium) and pump (ventricle) blood throughout a closed circulatory system. Here, we reveal a novel transcriptional pathway between foxn4 and tbx genes that facilitates this evolutionary event. We show that the zebrafish gene slipjig, which encodes Foxn4, regulates the formation of the atrioventricular (AV) canal to divide the heart. sli/foxn4 is expressed in the AV canal, and its encoded product binds to a highly conserved tbx2 enhancer domain that contains Foxn4-and T-box-binding sites, both necessary to regulate tbx2b expression in the AV canal.Supplemental material is available at http://www.genesdev.org.Received October 30, 2007; revised version accepted January 23, 2008. The evolution of organs and adaptation of specialized structures utilizes the duplication of highly conserved transcription factors and their cis-regulatory elements. Because of its gradual progression from a single-chambered muscular tube with peristaltic contractility (invertebrates) to a complex multichambered structure with diverse specialized cardiomyocytes (vertebrates), the heart is ideal to study the genetic underpinnings of organogenesis as well as the evolutionary basis of morphological complexity. Division of the heart into chambers represents an essential evolutionary milestone that allows for the heart to receive and pump blood throughout a closed circulatory system (for review, see Olson 2006). Initially, the vertebrate heart develops as a linear tube without significant cellular or physiological differences; however, as the heart tube loops, distinct cardiac chambers begin to develop and acquire high gap junction density leading to faster conduction velocities. In contrast, the atrioventricular (AV) canal and inner curvature regions expand more slowly and maintain characteristics of embryonic tubular hearts including slow conduction velocity (for review, see Moorman and Christoffels 2003). Due to its primitive myocardial nature, the AV canal has evolved several specialized functions in heart formation and function including the formation of AV cushions as well as AV cardiac conduction delay. Here we reveal how these evolutionarily specialized AV structures are coupled developmentally through a novel transcriptional circuit to structurally (AV valves) and functionally (AV conduction delay) separate the atrium and ventricle. Results and DiscussionFrom a recent ENU mutagenesis screen ), we identified a unique cardiovascular mutant, slipjig (sli) (Chen et al. 1996), which displays not only structural AV canal malformations but also AV conduction defects (Fig. 1). sli mutants appear indistinguishable from their wild-type siblings up to 30 h post-fertilization (hpf), displaying formation of a cardiac tube that pumps blood throughout the embryo (data not shown). However, by 36-48 hpf, sli mutants exhibit pericardial edema due to dysmorphic hearts that fail to loop and form an AV canal (Fig. 1A, and cf. B,D and C,E). Fur...
Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the developed world due to the limited capacity of adult mammalian ventricular cardiomyocytes to divide and replace ventricular myocardium lost from ischemia-induced infarct1,2. As a result, there is great interest to identify potential cellular sources and strategies to generate new ventricular myocardium3. Past studies have shown that lower vertebrate and early postnatal mammalian ventricular cardiomyocytes can proliferate to help regenerate injured ventricles4–6; however, recent studies have suggested that additional endogenous cellular sources may contribute to this overall ventricular regeneration3. Here, we have developed in the zebrafish a combination of fluorescent reporter transgenes, genetic fate-mapping strategies, and a ventricle-specific genetic ablation system to discover that differentiated atrial cardiomyocytes can transdifferentiate into ventricular cardiomyocytes to contribute to zebrafish cardiac ventricular regeneration. Using in vivo time-lapse and confocal imaging, we monitored the dynamic cellular events during atrial-to-ventricular cardiomyocyte transdifferentiation to define intermediate cardiac reprogramming stages. Importantly, we observed that Notch signaling becomes activated in the atrial endocardium following ventricular ablation, and discovered that inhibiting Notch signaling blocked the atrial-to-ventricular transdifferentiation and cardiac regeneration. Overall, these studies not only provide evidence for the plasticity of cardiac lineages during myocardial injury, but more importantly reveal an abundant new potential cardiac resident cellular source for cardiac ventricular regeneration.
Abstract-Here we report the discovery of a characteristic dense vascular network (DVN) in the tip portion of epididymal adipose tissue in adult mice. The DVN is formed by angiogenesis rather than by vasculogenesis, and has functional blood circulation. This DVN and its subsequent branching may provide a new functional route for adipogenesis. The recruitment, infiltration, and accumulation of bone marrow-derived LYVE-1 ϩ macrophages in the tip region are crucial for the formation of the DVN. Matrix metalloproteinases (MMPs) and the VEGF-VEGFR2 system are responsible not only for the formation of the DVN, but also for the recruitment and infiltration of LYVE-1 ϩ macrophages into the epididymal adipose tissue tip region. SDF-1, but not the MCP-1-CCR2 system, is a critical factor in recruitment and ongoing retention of macrophages in this area. We also demonstrate that the tip region of epididymal adipose tissue is highly hypoxic, and thus provides a microenvironment conducive to the high expression and enhanced activities of VEGF, VEGFR2, MMPs, and SDF-1 in autocrine and paracrine manners, to create an ideal niche for the recruitment, retention, and angiogenic action of macrophages. These findings shed light on the complex interplay between macrophage infiltration, angiogenesis, and adipogenesis in the tip region of adult epididymal adipose tissue, and provide novel insight into the regulation of alternative outgrowth of adipose tissue. (Circ Res. 2007;100:e47-e57.) Key Words: adipogenesis Ⅲ angiogenesis Ⅲ lymphatic vessel hyaluronan receptor 1 Ⅲ macrophages Ⅲ matrix metalloproteinases Ⅲ monocyte chemoattractant protein-1 Ⅲ vascular endothelial growth factor receptors A dipose tissue is a unique organ that has reversible growth depending on the balance of fat metabolism. 1 It is mainly composed of adipocytes supported by stromalvascular tissue, which contains vascular endothelial cells, macrophages, and poorly characterized stem cells. [2][3][4] Developmental growth of adipocytes through adipogenesis (defined as development of adipoblasts into differentiated adipocytes) is accompanied by the growth of vasculature in adipose tissue. 2,3 Recent studies using pharmacological agents or cell implantation have proposed that the growth of adipose tissue is angiogenesis-dependent. [5][6][7][8] However, little is known about the nature of how angiogenesis governs the growth of adipose tissue and, inversely, how the growth of adipose tissue affects the growth of vasculature.Macrophages are released from the bone marrow as immature monocytes and circulate in the blood before extravasation into their target tissues, where they differentiate into resident macrophages. Thus, macrophages are found in every tissue of the body and, depending on the local microenvironment, acquire specialized functions including phagocytosis, antigen presentation, tissue remodeling, and the secretion of a wide range of growth factors and cytokines. 9 The distribution and accumulation of macrophages in certain tissue are mediated by several CC chemok...
Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder involving diseased cardiac muscle. BIN1 is a membrane associated protein important to cardiomyocyte homeostasis and is down regulated in cardiomyopathy. We hypothesized that BIN1 could be released into the circulation and that blood-available BIN1 can provide useful data on the cardiac status of patients whose hearts are failing due to ARVC. Objective To determine whether plasma BIN1 can measure disease severity in patients with ARVC. Methods We performed a retrospective cohort study of 24 patients with ARVC. Plasma BIN1 levels were assessed for their ability to predict cardiac functional status and ventricular arrhythmias. Results Mean plasma BIN1 levels were decreased in ARVC patients with heart failure (15 ± 7 vs. 60 ± 17 in patients without heart failure, p<0.05; plasma BIN1 is 60±10 in non-ARVC normal controls). BIN1 levels correlated inversely with ventricular arrhythmia (R=−0.47, p<0.05), and low BIN1 correctly classified patients with advanced heart failure or ventricular arrhythmia (ROC Area under the curve, AUC, of 0.88±0.07). Low BIN1 also predicted future ventricular arrhythmias (ROC AUC of 0.89±0.09). In a stratified analysis, BIN1 could predict future arrhythmias in patients without severe heart failure (n=20) with an accuracy of 82 %. In the seven ARVC patients with serial blood samples, all of whom had evidence of disease progression during follow up, plasma BIN1 decreased significantly (decrease of 63 %, p<0.05). Conclusions Plasma BIN1 seems to correlate with cardiac functional status and presence or absence of sustained ventricular arrhythmias in a small cohort of ARVC patients and can predict future ventricular arrhythmias.
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