IL-6 loss causes ventricular dysfunction, fibrosis, reduced capillary density, and dramatically alters the cell populations of the developing and adult heart

Abstract

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.

ERBB2 Deficiency Alters an E2F-1-Dependent Adaptive Stress Response and Leads to Cardiac Dysfunction

“…Of particular interest, the ERBB2-dependent E2F-1 targets include several proteins involved in cardiac muscle contractility, conduction, maintenance of heart rate, cardiac homeostasis, adaptive stress response, hypertrophy, ventricle morphology, and vascular integrity that have previously been shown to play important roles in cardiac development and/or adult heart function. Cardiac tissue-specific ablation of a number of these pathways, such as ILK and AHR signaling, results in heart dysfunction and sudden death in animals, reinforcing the importance of the cardiac ERBB2/E2F-1 transcriptional program identified in our study (26)(27)(28)(29)(30)(31)(32). Of interest, thrombopoietin and ILK signaling, which have both been shown to protect against in vitro and in vivo anthracycline-induced cardiotoxicity (33,34), were modulated in the ERBB2-deficient hearts.…”

Systems Chemo‐Biology and Transcriptomic Meta‐Analysis Reveal the Molecular Roles of Bioactive Lipids in Cardiomyocyte Differentiation

“…This cytokine is secreted by cardiofibroblasts and functions in heart remodeling (Porter & Turner 2009). Cardiac cells that lack Il6 activity attenuated the activation of Stat3 and Vegfa production, leading to interstitial collagen accumulation, which promotes cardiac dilatation and ventricular dysfunction (Porter & Turner 2009;Banerjee et al 2009). In both the CP and CM networks, Cxcr4, Cxcl12 and Cxcl13 interacted directly with S1P (Fig.…”

The Cardiogenic Niche as a Fundamental Building Block of Engineered Myocardium

“…Members of the IL-6 family are also mainly secreted from cardiac fibroblasts and have been demonstrated to play an important role during cardiac development and postnatally for cardiomyocyte growth [Banerjee et al, 2009]. The biological activity of IL-6 is regulated by the transmembrane receptor subunit gp130, and continuous stimulation with IL-6 or other members of the IL-6 family, including leukemia inhibitor factor (LIF) and cardiotrophin (CT-1), leads to cardiac hypertrophy [Hirota et al, 1995].…”