TIMPs and cardiac remodeling: ‘Embracing the MMP-independent-side of the family’

Unraveling the biological role of tissue inhibitors of metalloproteinases (TIMPs) during cardiac remodeling and the progression of heart failure has proven to be an enormous challenge. Remodeling of the cardiac extracellular matrix (ECM), regulated by matrix metalloproteinases (MMPs) and their endogenous inhibitors, TIMPs, is a well-established paradigm in cardiac health and disease. Originally, TIMPs were thought to function exclusively as endogenous inhibitors of MMP activity, thereby fine-tuning MMP-mediated ECM degradation and numerous related processes. However, during the last two decades, the concept of MMP-independent TIMP-mediated receptor signaling and regulation of cell fate has emerged. Although our current knowledge is still limited, in this review, we highlight some of the novel data, illustrating the MMP-independent biological properties of the four TIMP family members. Moreover, we discuss how these cell-specific insights may contribute to the process of cardiac remodeling, disease and failure. Finally, we identify where additional research is needed that will codetermine the possible future of TIMPs as therapeutic targets.