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Relative roles of cell surface IP versus intracellular nuclear receptor PPARbeta in the sensing and signalling of prostacyclin

Final Activity Report Summary - IPvsPPARb (Relative roles of cell surface IP versus intracellular nuclear receptor PPARbeta in the sensing and signalling of prostacyclin)

Prostacyclin (PGI2) is a powerful endogenous mediator synthesised by endothelial cells following the consecutive actions of cyclo-oxygenase and PGI2 synthase. The actions of PGI2 are mediated by two receptor classes, namely cell surface IP receptors, linked to adenylate cyclase, and peroxisome proliferator-activated receptors (PPAR) beta/delta nuclear receptors, which regulate the transcription of several target genes to mediate cellular responses. However, the relative roles of IP versus PPARbeta/delta in the sensing and signalling of PGI2 by tissues of the cardiovascular system is unknown. Therefore, the main purpose of this project was to characterise the way in which IP and PPARbeta/delta receptor systems acted and interacted when cells were treated with PGI2 related compounds.

PGI2 and related compounds, i.e. treprostinil sodium (TS), were involved in the regulation of a number of biological processes including inhibition of platelet aggregation and vasodilation. The results of this project confirmed that PPARbeta/delta agonists could, in addition to inhibition of platelet aggregation, induce profound vasodilator effects and modulate innate immune function. The relative roles of IP and PPARbeta/delta receptors were confirmed by using genetic modified mice which were deficient for these receptors, i.e. IP-/- and PPARbeta/delta -/- mice, respectively. Our findings showed that both IP and PPARbeta/delta receptors played a key role in the effects that were induced by the PGI2 mimetic TS, whereas effects induced by the PPARbeta/delta agonists GW0742 were partially mediated by IP receptors but were independent of PPARbeta/delta receptors. Finally, the analysis of the mechanism by which PPARbeta/delta agonists induced dilator responses revealed the RhoA/rho kinase pathway as the main target for these drugs. This was illustrated using GW0742.

These data were the first to clearly identify a non-genomic function of PPARbeta/delta agonists in blood vessels. The vasodilator and anti-proliferative effects of PGI2-related compounds rendered these drugs as one of the principal therapeutic strategies for the treatment of pulmonary hypertension. The observation that PPARbeta/delta agonists were able to induce acute vasodilator effects in the pulmonary vascular bed was potentially very important, since it supported an earlier suggestion of our group that PPARbeta/delta agonists could be useful in the treatment of pulmonary hypertension. Finally, the identification of RhoA/rho kinase as the target for non genomic actions of GW0742 was novel and, after further experimentation, could have implications for the development of new therapies.

In summary, the results obtained during the present fellowship added invaluable information in our understanding regarding how PGI2 was sensed in the cardiovascular system and the role of IP and PPARbeta/delta receptors in these processes.