Investigations into the influence and role of tissue factor in the pathogenesis of myocardial hypertrophy

Recently it has been demonstrated that tissue factor (TF) plays an important role in the induction and/or progression of cardiac hypertrophy. The aim of this thesis was to examine the relationship between TF and the onset of cardiac hypertrophy. Cardiac hypertrophy was achieved by aortic constriction in male Sprague-Dawely rats. TF levels increased in cardiac tissue but not in isolated cardiomyocytes suggesting another cellular site of TF expression. In contrast, tissue factor pathway inhibitor, (TFPI), was transiently up-regulated in cardiomyocytes potentially to counteract the effects of TF. Stimulation of H9c2 cardiomyocytes with exogenous TF resulted in the up-regulation of mechano growth factor. Incubation of the cells with TF alone up-regulated atrial natriuretic factor (ANF) expression, whilst the presence of the TF-associated proteases, factor VIla and factor Xa, suppressed this effect, suggesting that contact between TF and blood within the heart can exacerbates the hypertrophic response. Moderate concentrations of TF were found to induce proliferation In H9c2 cardiomyocytes, while high concentrations of TF resulted in increased cellular apoptosis as detected by caspase-3 activation but via a p53-independent mechanism. In addition, supplementation of TF with proteolytically active factors, VIla and Xa, partially abrogated this apoptotic effect. These data suggest that the expression of moderate concentrations of TF, induced by pressure overload observed during early hypertrophy, result in an enhanced rate of cellular turnover, and combined with hypertrophic growth, leads to alterations in heart structure. In contrast, higher concentrations of TF at later stages of disease can deplete the cardiomyocytes. In conclusion, TF appears to function as a pro-inflammatory mediator which is upregulated at the onset of hypertrophy and is capable of influencing the progression of the disease through altering the function of cardiomyocytes.