In this study, we have demonstrated a new concept for treating heart failure and cardiac fibrosis, which addresses the urgent unmet need for novel and innovative therapies for treating these conditions. By using rats exposed to aortic banding, cultured cardiac fibroblasts and samples from heart failure patients, we have identified the extracellular matrix enzyme A disintegrin and metalloprotease with thrombospondin motif 4 (ADAMTS4) as a promising target for protection against heart failure and cardiac fibrosis. In aortic banding rats, treatment with an inhibitor of ADAMTS enzymes prevented development of cardiac fibrosis and dysfunction. In treated animals, we found a marked reduction in the myocardial collagen content and the expression in transforming growth factor (TGF)-β target genes. In vitro, we demonstrated that ADAMTS4 elicited a not previously known cleavage of TGF-β-binding proteins, i.e. latent-binding protein of TGF-β and extra domain A-fibronectin. This cleavage released TGF- β, thus explaining the effects on fibrosis and TGF- β activity in vivo. A marked increase in ADAMTS4 expression and activity in failing human hearts supports a translational potential for this treatment principle.