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postgraduate thesis: Pharmacological activation of biased soluble guanylyl cyclase activity in the blood vessel wall

TitlePharmacological activation of biased soluble guanylyl cyclase activity in the blood vessel wall
Authors
Issue Date2016
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Detremmerie, C. M. S.. (2016). Pharmacological activation of biased soluble guanylyl cyclase activity in the blood vessel wall. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractVascular tone is regulated by a complex interaction between endothelial and smooth muscle cells. The endothelium releases vasoactive substances influencing the contractile state of the underlying smooth muscle. The most extensively studied endothelium-derived vasoactive factor is nitric oxide (NO), which, although being known for its potent dilator effect by activating soluble guanylyl cyclase (sGC) to produce guansosine 3’,5’ cyclic monophosphate (cyclic GMP), has counterintuitively shown to be a vasoconstrictor signal under hypoxic conditions. Acute hypoxia augments contractions of isolated coronary arteries of pigs because the NO produced by endothelial NO synthase (eNOS) causes biased activation of sGC in the underlying vascular smooth muscle cells to produce inosine 3’,5’ cyclic monophosphate (cyclic IMP), rather than the canonical cyclic GMP. This non-canonical cyclic nucleotide augments vasoconstriction by modulating calcium homeostasis in smooth muscle cells. Preliminary studies have shown that quinones, natural compounds with anti-oxidant, anti-bacterial and anti-tumoral properties, cause an endothelium-dependent augmentation of contractions in isolated arteries, which is similar in characteristics to that caused by hypoxia. It thus seemed that quinones can be used as a pharmacological tool to examine augmentations of vasoconstrictions due to biased sGC activation. The objective of this thesis was to study the underlying mechanisms of quinone-induced augmentations in the systemic and pulmonary circulation of rats and pigs and to assess the effect of pathophysiological conditions [known to affect endothelium-dependent contractions (including ageing, obesity and hypertension)] on such augmentations. The results showed that the augmentations of contractions by quinones in isolated systemic arteries of rats and pigs depend on endothelium-derived NO activating sGC. As with hypoxia, quinones cause a biased activation of sGC producing cyclic IMP rather than cyclic GMP. The former affects calcium homeostasis in smooth muscle cells, activating voltage-dependent calcium influx and/or Rho-associated protein kinase (ROCK)-mediated calcium sensitization, depending on the species and the vascular bed studied, to cause augmentation. The findings suggest that quinones activate endothelial NAD(P)H:quinone acceptor oxidoreductase-1 (NQO-1), their metabolizing enzyme, thereby increasing the NAD^+/NADH ratio and eNOS-activity/smooth muscle contractility. Ageing and hypertension, but not obesity, decrease quinone-induced augmentations in isolated rat arteries, in part by causing endothelial dysfunction impairing NO bioavailability. The study of the effect of these pathophysiological conditions, therefore, also confirms the second identity of NO as a vasoconstrictor signal. In pulmonary arteries of rats, acute hypoxia causes augmentations that cannot be blocked by eNOS- and sGC-inhibitors but surprisingly can be augmented with exogenous NO, while quinones cause augmentations that depend on endothelium-derived NO and activation of sGC. Nevertheless, both pulmonary hypoxic and quinone-induced vasoconstriction involve the activation of NQO-1. Taken in conjunction, the studies reported in the thesis provide novel pharmacological evidence for the existence of endothelium-dependent contractions counterintuitively depending on NO and biased sGC activity with subsequent production of cyclic IMP. The results also permit the identification of cellular targets (NQO-1, voltage-dependent calcium channels and ROCK) for the development of novel therapies for the prevention of coronary vasospasm under hypoxic conditions, as observed in sleep apnea patients, but also possibly for the treatment of pulmonary hypertension.
DegreeDoctor of Philosophy
SubjectQuinone
Lungs - Blood-vessels
Dept/ProgramPharmacology and Pharmacy
Persistent Identifierhttp://hdl.handle.net/10722/255004

 

DC FieldValueLanguage
dc.contributor.authorDetremmerie, Charlotte Marie Simonne-
dc.date.accessioned2018-06-21T03:41:54Z-
dc.date.available2018-06-21T03:41:54Z-
dc.date.issued2016-
dc.identifier.citationDetremmerie, C. M. S.. (2016). Pharmacological activation of biased soluble guanylyl cyclase activity in the blood vessel wall. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/255004-
dc.description.abstractVascular tone is regulated by a complex interaction between endothelial and smooth muscle cells. The endothelium releases vasoactive substances influencing the contractile state of the underlying smooth muscle. The most extensively studied endothelium-derived vasoactive factor is nitric oxide (NO), which, although being known for its potent dilator effect by activating soluble guanylyl cyclase (sGC) to produce guansosine 3’,5’ cyclic monophosphate (cyclic GMP), has counterintuitively shown to be a vasoconstrictor signal under hypoxic conditions. Acute hypoxia augments contractions of isolated coronary arteries of pigs because the NO produced by endothelial NO synthase (eNOS) causes biased activation of sGC in the underlying vascular smooth muscle cells to produce inosine 3’,5’ cyclic monophosphate (cyclic IMP), rather than the canonical cyclic GMP. This non-canonical cyclic nucleotide augments vasoconstriction by modulating calcium homeostasis in smooth muscle cells. Preliminary studies have shown that quinones, natural compounds with anti-oxidant, anti-bacterial and anti-tumoral properties, cause an endothelium-dependent augmentation of contractions in isolated arteries, which is similar in characteristics to that caused by hypoxia. It thus seemed that quinones can be used as a pharmacological tool to examine augmentations of vasoconstrictions due to biased sGC activation. The objective of this thesis was to study the underlying mechanisms of quinone-induced augmentations in the systemic and pulmonary circulation of rats and pigs and to assess the effect of pathophysiological conditions [known to affect endothelium-dependent contractions (including ageing, obesity and hypertension)] on such augmentations. The results showed that the augmentations of contractions by quinones in isolated systemic arteries of rats and pigs depend on endothelium-derived NO activating sGC. As with hypoxia, quinones cause a biased activation of sGC producing cyclic IMP rather than cyclic GMP. The former affects calcium homeostasis in smooth muscle cells, activating voltage-dependent calcium influx and/or Rho-associated protein kinase (ROCK)-mediated calcium sensitization, depending on the species and the vascular bed studied, to cause augmentation. The findings suggest that quinones activate endothelial NAD(P)H:quinone acceptor oxidoreductase-1 (NQO-1), their metabolizing enzyme, thereby increasing the NAD^+/NADH ratio and eNOS-activity/smooth muscle contractility. Ageing and hypertension, but not obesity, decrease quinone-induced augmentations in isolated rat arteries, in part by causing endothelial dysfunction impairing NO bioavailability. The study of the effect of these pathophysiological conditions, therefore, also confirms the second identity of NO as a vasoconstrictor signal. In pulmonary arteries of rats, acute hypoxia causes augmentations that cannot be blocked by eNOS- and sGC-inhibitors but surprisingly can be augmented with exogenous NO, while quinones cause augmentations that depend on endothelium-derived NO and activation of sGC. Nevertheless, both pulmonary hypoxic and quinone-induced vasoconstriction involve the activation of NQO-1. Taken in conjunction, the studies reported in the thesis provide novel pharmacological evidence for the existence of endothelium-dependent contractions counterintuitively depending on NO and biased sGC activity with subsequent production of cyclic IMP. The results also permit the identification of cellular targets (NQO-1, voltage-dependent calcium channels and ROCK) for the development of novel therapies for the prevention of coronary vasospasm under hypoxic conditions, as observed in sleep apnea patients, but also possibly for the treatment of pulmonary hypertension. -
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshQuinone-
dc.subject.lcshLungs - Blood-vessels-
dc.titlePharmacological activation of biased soluble guanylyl cyclase activity in the blood vessel wall-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePharmacology and Pharmacy-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2017-
dc.identifier.mmsid991043962676103414-

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