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The initiation and progression of heart failure is linked to adverse cardiac remodeling of the extracellular matrix (ECM) during disease mainly through the deregulation of myocardial metalloproteinases (MMPs). Relaxin (RLX), a peptide hormone acting as a physiological cardiac effector, is a key regulator of ECM remodeling in reproductive and nonreproductive tissues. Studying primary cultures of mouse cardiac muscle cells and rat H9c2 cardiomyoblasts, we have obtained evidence for a new signaling pathway activated by RLX to induce ECM remodeling that involves the bioactive sphingolipids sphingosine-1-phosphate (S1P) and ceramide. In both cell populations, recombinant human RLX increased sphingosine kinase activity and S1P formation, whereas sphingomyelin and ceramide content were decreased in [3H]serine-labeled cells. According to the literature, RLX promoted MMP-2 and MMP-9 expression/release. Pharmacological inhibition of sphingolipid metabolism and silencing of sphingosine kinase 1, the enzyme responsible for S1P formation, were able to prevent MMP expression/release elicited by the hormone and induce the expression of tissue inhibitor of MMPs. In addition, we found that sphingolipid signaling is required for the regulation of connective tissue growth factor, a member of the CCN 1–3 family of genes that are involved in cell proliferation and differentiation. Finally, the induction of cardiomyoblast maturation induced by RLX was also found to be counteracted by inhibition of S1P formation. In conclusion, these findings provide a novel mechanism by which RLX acts on cardiac ECM remodeling and cardiac cell differentiation and offer interesting therapeutic options to prevent heart fibrosis and to favor myocardial regeneration.

Role of Sphingosine Kinase/S1P Axis in ECM Remodeling of Cardiac Cells Elicited by Relaxin