INVOLVEMENT OF THE 'TRACTION MODEL' AS TGF-BETA1 ACTIVATION MECHANISM IN THE DEVELOPMENT OF REACTIVE FIBROSIS IN SPONTANEOUSLY HYPERTENSIVE RATS CARDIAC FIBROBLASTS.

Cardiac reactive fibrosis is a well-known pathological effect derived from arterial hypertension. TGF-β plays a key role in the progression from the inflammation state to the fibrosis process establishment. Nonetheless, only the active form of TGF-β is effective, and this occurs if it is unbound to the latency complex proteins (i.e. Latency Associated Protein, LAP and Latent TGF-β Binding Protein, LTBP. In vivo and in vitro models of different fibrosis-based pathologies (e.g. pulmonary and dermal fibrosis), have highlighted a novelty in the activation of TGF–β, which occurs not only by proteolysis on latent proteins, which involves enzymes as plasmin, thrombospondin and matrix metalloproteases, but also through a non-proteolytic mechanism, defined by Keski-Oja in 2004 "Traction model". This mechanism consists in specific binding of several integrins (αVβ3, αVβ6 and αVβ5), expressed by myofibroblasts, with LAP and LTBP; contraction forces exerted by myofibroblasts are able to active latent TGF-β. On the basis of the “traction model” are an initial production of TGF-, the conversion of fibroblast into myofibroblast, the production of α-SMA by myofibroblast and their subsequent contractile activity, the increase in ECM production and, therefore, further TGF- production, in a positive feedback mechanism, able to amplify the fibrotic process progression. Aims of this study are 1) the development of a more fast and efficient protocol to cardiac fibroblast extraction, 2) the evaluation of possible involvement of LTBP-1 and αVβ5 integrin in development of hypertensive-induced cardiac fibrosis and so 3) the speculation about TGF-β1 mechanical activation by traction in primary cardiac fibroblasts isolated in hypertensive rats.