Reynolds, Louise Ellen; (2000) The role of integrins in mechano-transduction leading to enhanced collagen synthesis in human cardiac fibroblasts. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The mechanisms that regulate the development of cardiac hypertrophy and fibrosis are poorly understood. Cardiac hypertrophy results from changes in the mechanical environment and is accompanied by increased extracellular matrix (ECM) synthesis and remodelling. Collagen types I and III the major constituents of the ECM, have previously been shown to be increased during cardiac hypertrophy. In this study the importance of fibroblast: ECM interactions and subsequent activation of intracellular signalling pathways in the load-induced stimulation of collagen synthesis were investigated. More specifically the role of integrins as mechanotransducers was investigated. The data suggest that an interaction between human cardiac fibroblasts and a fibronectin matrix (rather than collagen or elastin) results in the most effective stimulation of procollagen synthesis when subjected to a cyclical mechanical load. Further, the addition of blocking antibodies to specific fibronectin integrins inhibited collagen synthesis induced by mechanical load, whereas blocking antibodies to a collagen integrin did not. These results suggest that fibronectin integrins act as mechanotransducers, allowing the mechanical stimulus to be transduced into a biochemical event. Conversion of the mechanical stimulus into a biochemical event appears to involve the formation of focal adhesion complexes. More specifically the focal adhesion proteins focal adhesion kinase (FAK), p130Cas, and the cytoskeleton associated protein paxillin, all showed increased tyrosine phosphorylation in response to mechanical load. Inhibitors of protein tyrosine phosphorylation not only prevented mechanical load induced tyrosine phosphorylation but also inhibited collagen synthesis. Inhibition of paxillin phosphorylation also suggests a role for the cytoskeleton in mechanical load activation of procollagen synthesis. Finally, experiments investigating the intracellular signalling pathways activated downstream of the focal adhesion complex showed that the MAP kinase and the phospholipid pathway may play a role in mediating the effects of mechanical load on procollagen synthesis. In conclusion, this thesis has shown for the first time that integrins act as mechanotransducers in human cardiac fibroblasts and that phosphorylation of FAK, as well as paxillin and p130Cas is required for mechanical load to be converted into signalling pathways leading to procollagen synthesis.

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