Patel, J; (2013) Smooth muscle cell proliferation and endothelin pathway in pulmonary arterial hypertension: Comparative effects of current and putative therapeutic agents. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Pulmonary arterial hypertension (PAH) is characterised by a progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular failure or a premature death. Its prevalence varies from 15-50 patients per million populations with an average age of 45 years. Prostacyclin (PGI2) analogues are used to treat PAH, but do not cure the condition. PGI2 binds to prostacyclin receptors (IP) in the cell membrane stimulating adenylate cyclase to increase intracellular cyclic 3’5’-adenosine monophosphate (cAMP). Once elevated, cAMP is rapidly broken down by phosphodiesterases (PDEs), specifically 1, 3, 4 which appear responsible for regulating levels in the lungs. One of the reasons for the ineffectiveness of PGI2 in PAH could be high activity of these PDE isoforms that specifically break down cAMP. So in chapter 3, I sought to evaluate the effect of prostacyclin analogues (e.g. treprostinil) on cAMP and cell proliferation in PAH. I was also interested to check whether phosphodiesterase inhibitors could potentiate the effects of PGI2 analogues. Elevated levels of endothelial ET-1 in idiopathic PAH have been shown to be correlated with increased right atrial pressure, pulmonary artery oxygen saturation and pulmonary vascular resistance. This has led to the use of ET-1 antagonists to treat PAH alone or in combination with other classical drugs. In chapter 4, I investigated the interaction between treprostinil, and endothelin antagonists on the ET-1 levels and growth characteristics of pulmonary smooth muscle cell cells (PASMCs) derived from IPAH patients. Vascular remodelling has been considered a pseudo-malignant disorder and mediators from cancer research have been described as targets for therapeutic interventions for PAH (Paulin et al., 2011). In chapter 5 I evaluated the antiproliferative effects of an already established anti-cancer drug ispinesib (Purcell et al., 2010) and thus established a rationale for investigating this agent in PAH settings.

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