Regulation of vascular mediators derived from hemeprotein

The aims of this thesis research were to examine possible regulatory functions of reactive compounds on PGI synthase and TxA synthase activity. This thesis showed that the activity of PGI synthase activity can be modified by "suicide" inactivation, a mechanism-based process that occurs during catalysis. Constitutive "suicide" regulation is rapidly compensated for in cultured cells by rapid de novo protein synthesis or through restoration of the heme prosthetic group. This compensatory process may be important for physiological homeostasis. The ability of cells to maintain the capacity to generate a potent vasodilatory and antiaggregatory substance may represent an endogenous mechanism to prevent thrombosis.;Nitric oxide, an unstable molecule, modulated the activity of PGI synthase and TxA synthase. NO regulated PGI synthase activity in a positive and negative fashion and was concentration dependent. NO also demonstrated a concentration dependent modulation of TxA synthase activity.;The results in this thesis research suggest that while PGI synthase and TxA synthase may depend on the enzymatic processes that produce substrate, this is not the only control point for the production of PGI$sb2$ and TxA$sb2.$ "Suicide" inactivation and de novo production of enzyme may play a role in inhibiting TxA$sb2$ production in platelets and maintaining PGI$sb2$ synthesis in endothelial cells. NO modulation may also tilt the balance of vasoactive mediators towards vasodilatory and antithrombotic state like aspirin.;The work described in this thesis also demonstrated that neither PGI synthase nor TxA synthase were significantly altered in a rat model of pulmonary hypertension. That patients with pulmonary hypertension exhibit decreased PGI$sb2$ production and PGI synthase levels, illustrates the importance of species variations. In certain instances, animal models of disease do not always exhibit appropriate parallels with human pathological conditions making it important to characterize animal models extensively.