Abstract
ATP can be released by and regulate the function of many cell types via the activation of membrane receptors. However, the release of ATP from cardiac fibroblasts (CF) has not been studied. We hypothesized that CF release ATP in response to physical perturbation, and that this release may be mediated by connexin (Cx) hemichannels. We isolated ventricular CF from adult Sprague Dawley rats, exposed them to hypotonic challenge or cyclic mechanical stress, and assayed extracellular media for ATP by a luciferin‐luciferase method. We found that hypotonic challenge and cyclic mechanical stretch increased ATP release from CF. Decreasing extracellular calcium from 1 mM to 0 mM, a maneuver that opens Cx hemichannel, increased ATP release, while carbenoxolone, a Cx blocker, markedly decreased ATP release. Real‐time PCR revealed that CF express multiple Cx proteins: Cx 43 > Cx 45 > Cx 40 and that TGF‐β treatment decreased expression of Cx 43 by 40%. We conclude that ATP release occurs from CF in response to hypotonic conditions and mechanical stretch and that this release likely occurs through Cx hemichannels, whose expression can be regulated by TGF‐β, a profibrogenic stimulus. Since CF and myocytes express receptors for ATP and its metabolites, release of ATP by CF likely contributes to autocrine/paracrine regulation of both fibroblasts and myocytes in the heart. (Supported by grants from NIH, AHA, and Ellison Medical Foundation)
Published Version
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