Interleukin-6 (IL-6) is a pleiotropic cytokine responsible for many different processes including the regulation of cell growth, apoptosis, differentiation, and survival in various cell types and organs, including the heart. Recent studies have indicated that IL-6 is a critical component in the cell-cell communication between myocytes and cardiac fibroblasts. In this study, we examined the effects of IL-6 deficiency on the cardiac cell populations, cardiac function, and interactions between the cells of the heart, specifically cardiac fibroblasts and myocytes. To examine the effects of IL-6 loss on cardiac function, we used the IL-6 −/− mouse. IL-6 deficiency caused severe cardiac dilatation, increased accumulation of interstitial collagen, and altered expression of the adhesion protein periostin. In addition, flow cytometric analyses demonstrated dramatic alterations in the cardiac cell populations of IL-6 −/− mice compared with wild-type littermates. We observed a marked increase in the cardiac fibroblast population in IL-6 −/− mice, whereas a concomitant decrease was observed in the other cardiac cell populations examined. Moreover, we observed increased cell proliferation and apoptosis in the developing IL-6 −/− heart. Additionally, we observed a significant decrease in the capillary density of IL-6 −/− hearts. To elucidate the role of IL-6 in the interactions between cardiac fibroblasts and myocytes, we performed in vitro studies and demonstrated that IL-6 deficiency attenuated the activation of the STAT3 pathway and VEGF production. Taken together, these data demonstrate that a loss of IL-6 causes cardiac dysfunction by shifting the cardiac cell populations, altering the extracellular matrix, and disrupting critical cell-cell interactions.
Cardiac fibroblasts, myocytes, endothelial cells and vascular smooth muscle cells are the major cellular constituents of the heart. Our recent studies have allowed us to observe alterations in the myocardial cell populations during development, in the adult animal and during disease using both surgical and genetic models. Whole hearts were isolated from mice during the neonatal and adult stages and single cell suspensions were prepared. Heterogeneous cell populations were immunolabeled for specific cell types and examined using Fluorescence Activated Cell Sorting (FACS) analyses. In addition, the left ventricle, right ventricle and septa were isolated, fixed and sectioned for morphometric analyses. These same cardiac regions were analyzed using FACS analyses. We observed that the adult murine myocardium is composed of approximately 56% myocytes, 27% fibroblasts, 7% endothelial cells and 10% vascular smooth muscle cells. Moreover, our morphometric and FACS data demonstrated similar percentages in both analyses. Furthermore, our current studies have demonstrated dramatic cardiac cell population shifts in IL‐6‐ and periostin‐deficient mice, as well as in a pressure overload hypertrophy model. Taken together, these data have enabled us to establish a homeostatic model for the myocardium that can be compared to other genetic and cardiac disease models.
In vertebrates, the regulation of cardiac myocyte proliferation has been attributed to FoxO transcription factors, which are mediated by PI3K/AKT signaling. The aim of this study was to identify the effects of altered PI3K/AKT signaling on heart development in Ciona intestinalis. We hypothesized that altered PI3K/AKT signaling would disrupt Ciona heart formation due to reduced proliferation of cardiac myocytes. In order to determine the developmental impact of altered PI3K/AKT signaling, Ciona larvae were generated via timed in vitro fertilization and then treated with drugs to specifically alter PI3K/AKT signaling. Ciona larvae were treated with drugs during the period of morphogenesis, which encompasses heart formation. Preliminary results show altered heart morphogenesis and delayed development in Ciona juveniles treated with the PI3K‐specific inhibitor in comparison to those treated with the other drugs or non‐treated controls. In addition, the size of hearts in Ciona juveniles treated with an AKT‐specific inhibitor was significantly reduced. Furthermore, increased expression of ciFoxO was observed in juveniles treated with AKT‐specific inhibitor. Future directions include the use of real time RT‐PCR to assay ciFoxO transcriptional activity and the utilization of immunohistochemistry to detect proliferation and apoptosis rates in the hearts of treated Ciona.
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