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Title: Targeting multidrug resistance proteins and C-type natriuretic peptide to optimise cyclic GMP signalling in cardiovascular disease
Author: Grange, Robert Matthew Henry
ISNI:       0000 0004 7652 277X
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2016
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Cyclic-3',5'-guanosine monophosphate (cGMP) is a fundamental intracellular signalling molecule that regulates vascular homeostasis through the tight control of vascular smooth muscle cell (VSMC) reactivity (i.e. vasoconstriction/relaxation) and proliferation. Aberrant VSMC growth and sustained vasoconstriction are hallmarks of cardiovascular disease, exemplified by pulmonary hypertension (PH). Multidrug resistance proteins (MRPs) are membrane bound transporters that facilitate cGMP cellular export thereby representing a potential mechanism that regulates intracellular cGMP-driven signalling. C-type natriuretic peptide (CNP) is an important vasoactive peptide released from the endothelium that maintains vascular homeostasis. CNP binds to natriuretic peptide receptor-B (NPR-B), generating cGMP, and NPR-C, which acts as a clearance receptor removing CNP from the circulation and a signalling pathway regulating vascular function via a cGMP-independent mechanism. Herein, I investigated two separate hypotheses: that MRPs play an important role in maintaining vascular homeostasis, and that endothelium-derived CNP and its cognate receptor, NPR-C, protects against the development of PH. The role of MRPs in regulating vascular homeostasis was investigated using organ bath pharmacology, human VSMC (hVSMC) proliferation and measuring mean arterial blood pressure (MABP) in conscious and anaesthetised mice. To investigate the role of endothelium-derived CNP and NPR-C in PH, male and female CNP and NPR-C knockout (KO) mice were used in two experimental models of PH: hypoxia plus Sugen5416 (SU5416) and bleomycin-induced. The severity of PH was measured using right ventricular systolic pressure (RVSP), MABP, right ventricular hypertrophy (RVH) and pulmonary vascular remodelling. MRP inhibition resulted in concentration-dependent vasorelaxation of mouse aorta per se and increased the potency of cGMP-dependent vessel relaxation in response to activation of both particulate and soluble guanylate cyclases (pGC and sGC). MRP inhibition alone also caused concentration-dependent attenuation of hVSMC proliferation, and enhanced cGMP-mediated attenuation of hVSMC growth via pGC and sGC activation. MRP inhibition per se did not decrease MABP in either anaesthetised or telemeterised mice. However, MRP inhibition did dose-dependently enhance reductions in MABP due to pGC activation in anaesthetised mice. Deletion of endothelial cell-derived CNP (ecCNP KO) in male and female mice did not result in any significant differences in RVSP, RVH or pulmonary vascular remodelling between WT and KO in the hypoxia plus SU5416 model of PH. However, global deletion of NPR-C in both male and female mice caused a significant increase in RVH but not RVSP or vascular remodelling when compared to WT. Both male and female NPR-C KO mice developed significantly increased RVSP compared to WT in the bleomycin-induced model of PH. However, only females exhibited a significant increase in RVH and lung weight in addition to RVSP. In conclusion, MRP inhibition demonstrates potential therapeutic utility to treat cardiovascular diseases by potentiating the vasodilatory and VSMC antiproliferative actions of natriuretic peptides and nitric oxide. Endothelial cellderived CNP is not essential to host protection against PH, whereas its cognate receptor NPR-C demonstrates a cardioprotective capacity. NPR-C attenuates bleomycin-induced PH in both males and females, with a greater effect observed in females. Overall, NPR-C agonism could potentially be used to ameliorate the cardiac and vascular pathology associated with PH.
Supervisor: Not available Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine & Dentistry ; Cardiovascular disease