Thrombospondins, Potential Drug Targets for Cardiovascular Diseases

The thrombospondin (TSP) family consists of five multimeric, multidomain calcium-binding glycoproteins that act as regulators of cellcell and cellmatrix associations as well as interact with other extracellular matrix molecules affecting their function. Increasing interest on cardiac TSP-1, TSP-2 and TSP-4 has emerged, and they have been studied in cardiac hypertrophy, myocardial infarction, heart failure, atherosclerosis and aortic valve stenosis. The aim of this MiniReview is to summarize the current knowledge on each TSP in various cardiovascular pathologies. We specifically emphasize the role of TSPs in cardiac remodelling and evaluate TSPs as potential cardiovascular drug targets. Thrombospondin-1 (TSP-1) is the most studied TSP, being antiangiogenic and able to activate transforming growth factor-beta. The functions of TSP-2 and TSP-4 are linked in maintaining the composition of the matrix of the hypertrophied heart, whereas there is very little knowledge on cardiac TSP-3 and TSP-5. TSP-1, TSP-2 and TSP-4 have been shown to affect cardiac remodelling in vivo, for example, by modulating matrix metalloproteinase and transforming growth factor-beta activity, collagen synthesis, myofibroblast differentiation, cell death and stretch-mediated augmentation of cardiac contractility. The detrimental role for TSPs in cardiovascular pathophysiology has been clearly demonstrated in knockout mouse models, and augmentation of TSP signalling in the heart during stress and haemodynamic overload might be beneficial. In conclusion, the role of TSP-1, TSP-2 and TSP-4 in cardiac hypertrophy, remodelling after myocardial infarction, heart failure, atherosclerosis and aortic valve stenosis encourages further investigation to validate them as potential drug targets.