We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Inhibition of the extracellular enzyme A disintegrin and metalloprotease with thrombospondin motif 4 prevents cardiac fibrosis and dysfunction.
- Authors
Vistnes, Maria; Erusappan, Pugazendhi Murugan; Sasi, Athiramol; Nordén, Einar Sjaastad; Bergo, Kaja Knudsen; Romaine, Andreas; Lunde, Ida Gjervold; Zhang, Lili; Olsen, Maria Belland; Øgaard, Jonas; Carlson, Cathrine Rein; Wang, Christian Hjorth; Riise, Jon; Dahl, Christen Peder; Fiane, Arnt Eltvedt; Hauge-Iversen, Ida Marie; Espe, Emil; Melleby, Arne Olav; Tønnessen, Theis; Aronsen, Jan Magnus
- Abstract
Aims Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such as fibrosis. We investigated whether the ECM enzyme known as A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) 4 might serve as a therapeutic target in treatment of heart failure and cardiac fibrosis. Methods and results The effects of pharmacological ADAMTS4 inhibition on cardiac function and fibrosis were examined in rats exposed to cardiac pressure overload. Disease mechanisms affected by the treatment were identified based on changes in the myocardial transcriptome. Following aortic banding, rats receiving an ADAMTS inhibitor, with high inhibitory capacity for ADAMTS4, showed substantially better cardiac function than vehicle-treated rats, including ∼30% reduction in E/e′ and left atrial diameter, indicating an improvement in diastolic function. ADAMTS inhibition also resulted in a marked reduction in myocardial collagen content and a down-regulation of transforming growth factor (TGF)-β target genes. The mechanism for the beneficial effects of ADAMTS inhibition was further studied in cultured human cardiac fibroblasts producing mature ECM. ADAMTS4 caused a 50% increase in the TGF-β levels in the medium. Simultaneously, 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. These effects were abolished by the ADAMTS inhibitor. In failing human hearts, we observed a marked increase in ADAMTS4 expression and cleavage activity. Conclusion Inhibition of ADAMTS4 improves cardiac function and reduces collagen accumulation in rats with cardiac pressure overload, possibly through a not previously known cleavage of molecules that control TGF-β availability. Targeting ADAMTS4 may serve as a novel strategy in heart failure treatment, in particular, in heart failure with fibrosis and diastolic dysfunction.
- Subjects
HEART fibrosis; EXTRACELLULAR enzymes; HEART failure; TRANSFORMING growth factors; FIBRONECTINS; EXTRACELLULAR matrix
- Publication
Cardiovascular Research, 2023, Vol 119, Issue 10, p1915
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvad078