SLC41A1 knockdown inhibits angiotensin II-induced cardiac fibrosis by preventing Mg2+ efflux and Ca2+ signaling in cardiac fibroblasts

Abstract Na + /Mg 2+ exchanger plays an important role in cardiovascular system, but the molecular mechanisms still largely remain unknown. The Solute Carrier family 41A1 (SLC41A1), a novel Mg 2+ transporter, recently was found to function as Na + /Mg 2+ exchanger, which mainly regulates the intracellular Mg 2+ ([Mg 2+ ] i ) homeostasis. Our present studies were designed to investigate whether SLC41A1 impacts on the fibrogenesis of cardiac fibroblasts under Ang II stimulation. Our results showed that quinidine, a prototypical inhibitor of Na + /Mg 2+ exchanger, inhibited Ang II-induced cardiac fibrosis via attenuating the overexpression of vital biomarkers of fibrosis, including connective tissue growth factor (CTGF), fibronectin (FN) and α-smooth muscle actin (α-SMA). In addition, quinidine also decreased the Ang II-mediated elevation of concentration of intracellular Ca 2+ ([Ca 2+ ] i ) and extrusion of intracellular Mg 2+ . Meanwhile, silencing SLC41A1 by RNA interference also impaired the elevation of [Ca 2+ ] i , [Mg 2+ ] i efflux and the upregulation of CTGF, FN and α-SMA provoked by Ang II. Furthermore, we found that Ang II-mediated activation of NFATc4 translocation decreased in SLC41A1-siRNA cells. These results support the notion that rapid extrusion of intracellular Mg 2+ is mediated by SLC41A1 and provide the evidence that the intracellular free Ca 2+ concentration is influenced by extrusion of intracellular Mg 2+ which facilitates fibrosis reaction in cardiac fibroblasts.