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Title: The potential role for PPAR beta/delta agonists in the treatment of pulmonary arterial hypertension
Author: Reed, Anna Katja
ISNI:       0000 0004 2706 1559
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Idiopathic Pulmonary Arterial Hypertension (iPAH) is a devastating, progressive disease with an appalling prognosis. It is characterised pathologically by the histological triad of pulmonary artery vasoconstriction, intraluminal thrombus formation and hypertrophy of the vascular smooth muscle surrounding the blood vessel. Prostacyclin was the first effective therapy to be introduced for the treatment of pulmonary arterial hypertension. It is a potent pulmonary artery vasodilator, has anti-platelet, and therefore anti-thrombotic effects. it also has anti-proliferative effects on vascular smooth muscle cells. Prostacyclin was introduced in the mid 1990's and until recently was the only therapy proven to improve outcome in terms of both morbidity and mortality in this disease. Prostacyclin therapy is limited however, in that it is extremely expensive and complicated to administer. Recent data from our group suggests that some therapeutic effects of prostacyclin may occur via the nuclear PPAR β/δ receptor. PPAR β/δ agonists are available as a tablet that can be taken once daily and are relatively free of side effects. The ability to harness the some of the therapeutic benefits of prostacyclin via a safe and inexpensive oral preparation would be a real step forward in the management of these patients. This thesis aims to investigate the potential role for specific PPAR β/δ agonists as a new therapeutic target in pulmonary hypertension. and contains both in-vitro and in-vivo models. Initial experiments were designed to examine the effects of the PPAR β/δ agonists on vascular responses in-vitro and confirmed a profound vasodilator effect particularly on pulmonary arterial tissue. This is an exciting and novel observation and was followed up by further experiments to identify the mechanism by which this occurs. A chronic hypoxia rat model of pulmonary hypertension was employed to examine the effects of the PPAR β/δ agonists in-vivo and the data presented in this thesis shows robust protective effects on the development of right ventricular hypertrophy as well as trends towards a reduction in right ventricular systolic pressure and mean pulmonary artery pressure. Further studies using ELISAs were utilised to implicate RhoA, but not guanylate or adenylate cyclase in the dilator actions of PPAR β/δ in blood vessels. Some limited studies addressed how PPAR β/δ agonists affect endothelial cell proliferation. The data presented in this thesis shows that PPAR β/δ agonists have profound dilator effects on pulmonary artery tissue in-vitro and that in an in-vivo model of pulmonary hypertension, these agonists protect the right ventricle and may reduce right ventricular and pulmonary pressures. PPAR β/δ agonists may represent a novel therapy for the treatment of patients with pulmonary hypertension.
Supervisor: Mitchell, Jane ; MacKenzie, Louise ; Wort, John ; Zhao, Lan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available