In our latest publication in Communications Biology, we reveal an essential role of ADAMTSL3, an extracellular protein of unknown function, in maintaining cardiac structural and functional integrity in the failing heart. By regulating a central heart failure signalling pathway, the TGFβ mediated activation of cardiac fibroblasts, ADAMTSL3 emerges as a potential therapeutic target for this deadly syndrome.
During heart failure progression the myocardium remodels to counteract the harmful stimuli. The extracellular matrix in-between cardiac muscle cells is crucial for maintaining cardiac structural and functional integrity, and an integral part of the remodelling response. In heart failure, cardiac fibroblasts are activated by the signalling molecule ‘transforming growth factor (TGF)β’, and transdifferentiate into highly proliferating and matrix-producing ‘myofibroblasts’, which drives pathological cardiac fibrosis. TGFβ thus represents an attractive therapeutic target, however, direct TGFβ inhibition is limited by adverse effects, warranting a better understanding of TGFβ regulation in the failing heart. In the present study, the role of the matrix glycoprotein ADAMTSL3 in heart failure was investigated through generation of a Adamtsl3 knock-out mouse. Importantly, the investigators discovered that the knock-out mice develop contractile dysfunction and cardiac dilatation, with high mortality, after aortic constriction, showing that ADAMTSL3 plays a crucial role in the failing heart. Molecular analysis revealed increased TGFβ activity and presence of myofibroblasts in the knock-outs, with increased levels of insoluble collagen, indicating a stiffer extracellular matrix. ADAMTSL3 was subsequently confirmed to inhibit TGFβ activity, myofibroblast differentiation, and extracellular matrix production in cultured human cardiac fibroblasts.
The study identifies ADAMTSL3 as an important part of the cardiac extracellular matrix, with an essential role in preserving cardiac function in the failing heart. As a negative regulator of the pro-fibrotic driver TGFβ, ADAMTSL3 may hold therapeutic potential for heart failure patients, and future investigations will reveal whether ADAMTSL3 has beneficial effects in the failing heart.