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Title: The effects of PPARβ/δ ligands on lung inflammation and vascular reactivity
Author: Perez Diaz, Noelia
ISNI:       0000 0004 9350 0097
Awarding Body: University of Hertfordshire
Current Institution: University of Hertfordshire
Date of Award: 2020
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The peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a transcription factor ubiquitously expressed in cells, although more highly active in skeletal muscle, arteries and endothelium. Signalling via PPARβ/δ is involved in lipid metabolism, glucose metabolism, insulin sensitivity, inflammation, and cell proliferation and therefore it is emerging as a therapeutic target for the treatment of disorders associated with metabolic syndrome or diabetes. However, there are great discrepancies in the literature about the role of PPARβ/δ and scientists describe both anti- and pro-effects on inflammation, cell migration and cell proliferation after ligand-activation of PPARβ/δ. Understanding the PPARβ/δ mode of action is of great interest and may provide new molecular mechanisms for treating a variety of inflammation-related diseases. This thesis aims to expand the knowledge on PPARβ/δ to better understand its mechanism of action at genomic and non-genomic level, which might give some clues for new therapeutic drug developments targeting PPARβ/δ. Methods: Pharmacological techniques including organ bath and myography were used for the study of the non-genomic effects of PPARβ/δ on vascular tone, comparing aorta and mesenteric arteries as a model of systemic and resistance vasculature respectively from healthy and streptozotocin (STZ)-induced diabetic rats. Molecular biology techniques including Griess assay, ELISA and qRT-PCR were used for the study of the regulation of lung inflammation by PPARβ/δ, focusing on the PPARβ/δ molecular switch between induction and trans-repression, two different pathways of gene regulation. Computational methods such as docking were used for the study of the PPARβ/δ binding pocket and how PPARβ/δ is activated/repressed after ligand binding as well as the possibility of accommodating more than one ligand simultaneously into the binding pocket. Results: In large STZ-diabetic systemic aorta arteries, PPARβ/δ inhibits the contraction through the PI3K/Akt/eNOS pathway. GW0742, a PPARβ/δ agonist, improves vasodilation through the RhoA/ROCK pathway in Naïve aorta and through potassium channels in STZ-diabetic aorta. In resistance arteries such as mesenteric arteries, PPARβ/δ inhibits the contraction through the PI3K/Akt/eNOS pathway in Naïve and possibly STZ-diabetic tissues. In contrast, GW0742 inhibits the RhoA/ROCK pathway on STZ-diabetic mesentery arteries and regulates the potassium channels in Naïve mesenteric arteries in a PPARβ/δ independent manner. In the model of lung inflammation used, the presence of agonist (GW0742 or L-165041) and antagonist (GSK3787 or GSK0660) at same time has anti-inflammatory effects and switches the PPARβ/δ mode of action from induction to trans-repression, therefore it was concluded that, at least in this model, the PPARβ/δ induction mode of action is pro-inflammatory and the trans-repression anti-inflammatory. PPARβ/δ agonists and antagonists bind differently to the PPARβ/δ receptor pocket. PPARβ/δ agonists form polar interactions with the residues His287, His413 and Tyr437 whilst PPARβ/δ antagonists form polar interactions with the residues Thr252 and Asn307. Further, our modelling indicates favourable binding energies and the feasibility of two ligands binding at same time into the PPARβ/δ binding pocket. Conclusion: A multidisciplinary approach was designed for the study of PPARβ/δ and provided novel information about its functioning both at genomic and non-genomic level. The findings of this thesis can help the drug discovery industry for a better prediction of the modelling behaviour of new PPARβ/δ drugs and can support the rationale for developing new treatments targeting PPARβ/δ for hypertension and/or cardiovascular complications.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: PPARß/d ; molecular switch ; inflammation ; diabetes ; RXR ; NF-?B ; lung ; pulmonary artery ; mesenteric artery ; aorta ; bronchi ; GW0742 ; GSK3787 ; vascular reactivity ; myography ; docking ; RhoA/ROCK ; PI3K/Akt/eNOS