Kiernan, Linda Alice; (1998) The role of the renin angiotensin system in regulating collagen deposition in the development of cardiac fibrosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The mechanisms that regulate the development of the cardiac hypertrophy and fibrosis that accompany systemic hypertension are not clear, but both the elevated BP itself and the renin angiotensin system (RAS) have been implicated. In this study the relative roles of BP and the RAS in regulating left ventricular hypertrophy (LVH) and cardiac fibrosis were investigated using the hypertensive transgenic (mRen2)27 rat (TGR). The results obtained suggest that development of LVH and fibrosis in the TGR are regulated by BP and not RAS activity. Since cardiac fibroblasts are the major cells responsible for collagen production, myocardial fibroblast cultures from TGR and control Sprague Dawley (SD) rats were established to determine the mechanisms responsible for collagen accumulation in the hypertensive heart. Basal levels of replication and procollagen production and the response of cells to growth factors were compared in TGR and SD fibroblasts. The results suggest that the increased collagen deposition in TGRs is due to increased collagen production rather than decreased degradation or increased fibroblast replication. All does not appear to be involved in the enhanced collagen synthesis observed in the TGR fibroblasts, since the responses of TGR and SD cells to RAS agonists and antagonists were not significantly different and RAS antagonists failed to reduce TGR collagen synthesis to SD levels. These results are in agreement with the in vivo results of this study, in which BP rather than the RAS appeared to be the main factor involved in the development of cardiac fibrosis in the TGR rat. Finally, this study demonstrated that in the TGR rat tissue ACE inhibition protects against the development of the malignant hypertensive (MH) phenotype, death associated with this condition and appearance of some of the renal histopathological features associated with MH. These protective effects appear to be independent of any reduction in SBP.

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