Papakrivoupoulou, Eugenia Spyridoula; (2001) The role of MAP kinases in the regulation of mechanical load-induced procollagen gene expression in cardiac fibroblast. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The cells of the cardiovascular system are continuously subjected to mechanical forces due to changes in blood volume and pressure. When these forces increase, during pathophysiological conditions such as hypertension or valvular disease, tissue remodelling occurs in an effort to adapt to these changes. In vivo, this remodelling involves enlargement of myocytes, proliferation of fibroblasts and increased deposition of extracellular matrix proteins such as collagen. The development of devices whereby mechanical load can be applied to cells in culture, has allowed the study of the mechanisms underlying these processes. Studies of myocytes have demonstrated that mechanical loading induces cell hypertrophy and activation of a genetic program (e.g. activation of c-jim and c-fos) similar to that seen in the hypertrophic myocardium in vivo. Furthermore, in cardiac myocytes, the signal transduction pathways mediating these responses are now being elucidated. Studies have shown that members of a family of protein kinases known as the mitogen activated protein kinase (MAPK) family, are important mediators of the hypertrophic response in myocytes. In fibroblasts, studies in this laboratory have demonstrated that mechanical load stimulates cardiac fibroblast procollagen ai (I) gene expression and synthesis. However, although the effects of mechanical load on fibroblast function are becoming increasingly documented, the signal transduction pathways that mediate these responses are less well understood. The hypothesis of this thesis was that one or more of the MAP kinases are activated by mechanical load, leading to an upregulation in procollagen ai (I) gene expression. The results show that mechanical load results in a rapid and transient activation of all three members of this family examined, ERK 1/2, JNK and p38 kinase. ERK 1/2 and p38 kinase were also found to translocate to the nucleus following mechanical loading. Activation of the ERK 1/2 pathway was found to be necessary but not sufficient for the mechanical load-induced upregulation of procollagen ai (I) gene expression - using two specific inhibitors of the activation of this kinase abrogated this response, but activation of ERK 1/2 alone was not sufficient to induce an upregulation of gene expression. Load-induced activation of ERK 1/2 was found to be PKC- and tyrosine kinase-independent. Procollagen ai (I) gene expression however, was found to be tyrosine kinase-dependent. Inhibition of p38 kinase activity resulted in an increase in both basal and stretch-stimulated levels of procollagen ai (I) mRNA suggesting that this pathway is involved in the negative regulation of procollagengene expression. In summary, this thesis demonstrates for the first time that ERK 1/2, JNKs and p38 MAP kinases are important components of the signal transduction pathways stimulated by mechanical load in cardiac fibroblasts. However, in relation to their role in regulating procollagen gene expression in response to this stimulus, ERK 1/2 appears stimulatory, whereas p38 kinase has an inhibitory effect.

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