Inflammatory activation of human cardiac fibroblasts leads to altered calcium signaling, decreased connexin 43 expression and increased glutamate secretion

Eva Skiöldebrand; Annika Lundqvist; Ulrika Björklund; Mikael Sandstedt; Anders Lindahl; Elisabeth Hansson; Lillemor Mattsson Hultén

doi:10.1016/j.heliyon.2017.e00406

Inflammatory activation of human cardiac fibroblasts leads to altered calcium signaling, decreased connexin 43 expression and increased glutamate secretion

Heliyon. 2017 Oct 3;3(10):e00406. doi: 10.1016/j.heliyon.2017.e00406. eCollection 2017 Oct.

Authors

Eva Skiöldebrand¹, Annika Lundqvist², Ulrika Björklund³, Mikael Sandstedt¹, Anders Lindahl¹, Elisabeth Hansson³, Lillemor Mattsson Hultén²

Affiliations

¹ Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
² Department of Molecular and Clinical Medicine, Wallenberg Laboratory, the Sahlgrenska Academy, University of Gothenburg, Sweden.
³ Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden.

Abstract

Cardiac fibroblasts, which are abundant in heart tissue, are involved not only in extracellular matrix homeostasis and repair, but also in cardiac remodeling after a myocardial infarction that, in turn, can lead to loss of cardiac function and heart failure. Ca²⁺ signaling is functionally important in many cell types, but the roles of fibroblast signaling and inflammation in the pathogenesis of heart disease are unclear. Here, we tested the hypothesis that inflammatory activation affects cardiac fibroblasts, both in terms of Ca²⁺ signaling and their capacity for intercellular communication through the gap junction channel protein connexin 43 (Cx43). We examined Ca²⁺ responses induced by known modulators of cardiac function such as glutamate, ATP and 5-hydroxytryptamine (5-HT) in human cardiac fibroblasts, under normal and inflammatory conditions. We showed that activation of human cardiac fibroblasts by lipopolysaccharide (LPS) for 24 h altered Ca²⁺ signaling, increased TLR4 and decreased Cx43 expression. In the fibroblasts, LPS treatment increased glutamate-evoked and decreased 5-HT-evoked Ca²⁺ signals. LPS activation also induced increased secretion of glutamate and proinflammatory cytokines from these cells. In summary, we propose that inflammatory stimuli can affect intracellular Ca²⁺ release, Cx43 expression, glutamate release and cytokine secretion in human cardiac fibroblasts. Inflammatory conditions may, therefore, impair intercellular network communication between fibroblasts and cardiomyocytes potentially contributing to cardiac dysfunction.

Keywords: Biochemistry; Biological sciences; Cardiology; Cell biology; Health sciences; Immunology; Internal medicine; Medicine.