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

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.

Structural alterations and inflammation in the heart after multiple trauma followed by reamed versus non-reamed femoral nailing

“…Alterations in mRNA expression of Cx40, Cx43 and Cx45 were demonstrated previously after skeletal muscle crush injuries and were associated with regeneration and repair of damaged myofibers [34]. In presence of PTC, the mRNA expression of Cx43 increased in murine HL-1 cells, which might be mediated via toll-like receptor and NLRP3-inflammasome signalling as described previously [35,36]. Therefore, the inflammatory response due fracture stabilization (reamed vs. non-reamed) might result in alterations of the cell-cell contact and therefore myocardial damage.…”

Biochemical alterations in inflammatory reactive chondrocytes: evidence for intercellular network communication

“…Rather, they are equipped with Ca 2+ signaling systems that can be inter-and/or extracellular in nature. Our results show time-dependent Ca 2+ responses of chondrocytes to glutamate, 5-HT, and ATP; this mimics the response of astrocytes in the central nervous system, which is one of the most well studied network-coupled cell systems and cardiac fibroblast [ 27 , 45 , 46 ]. Cells cultured in monolayer are prone to dedifferentiate, which could confound interpretation of results.…”

Low-grade inflammation causes gap junction-coupled cell dysfunction throughout the body, which can lead to the spread of systemic inflammation

“…TLR4 is most likely present on all cells involved in immune function [26], including gap junctioncoupled cells. Examples of these cells include chondrocytes [30], cardiac fibroblasts [31], keratinocytes [32], and tenocytes [33]. TLRs are involved in the pathogenesis of autoimmune disease, chronic inflammatory and infectious diseases, leading to overproduction of autoantibodies [34].…”

“…Cardiac fibroblasts in heart tissue communicate by Ca 2+ signaling through gap junction channel Cx43 protein [31] (Fig. 2).…”