ATP release and activation of P2Y2 receptors in the regulation of cardiac fibroblasts

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Cardiac fibroblasts (CFs), which play an essential role in cardiac remodeling, are activated and convert to a pro‐fibrotic phenotype in response to a variety of extracellular factors, including nucleotides. In previous work we showed that activation of P2Y2 (nucleotide) receptors is pro‐fibrotic. Here, using CFs isolated from adult rats and mice, we assessed ATP release and receptor activation by released ATP. We find that hypotonic conditions rapidly produce a ~10‐fold increase in extracellular ATP concentration. Rat CFs express connexins (Cxˈs) 43 and 45, which both, based on knockdown with siRNA, contribute to ATP release. Released ATP activates ERK via P2Y2 receptors; this activation is blunted by treatments that inhibit ATP release: carbenoxolone, apyrase and Cx siRNA. Pharmacological inhibition of ERK and knockout of P2Y2 receptors both decrease ATP‐stimulated increases in collagen production and expression of pro‐fibrotic markers, e.g., plasminogen activator inhibitor‐1 (PAI‐1) and monocyte chemotactic protein‐1 (MCP‐1). The pro‐fibrotic response to released extracellular ATP via P2Y2 receptors and ERK thus is an autocrine/paracrine mechanism that likely contributes to CF activation in response to cardiac injury. Supported by grants from NIH (GM007752, HL980621, HL066941, GM066232).