Investigating the role of nitrite in cardiovascular disease

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Goodwin, Joanna Jane (2018). Investigating the role of nitrite in cardiovascular disease. University of Birmingham. M.Sc.

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Abstract

Nitrite exerts potent vasodilatory effects during hypoxic and normoxic conditions and is known to elicit cardioprotection. Nitrite produces nitric oxide (NO) during hypoxic conditions, but normoxic signalling still remains unclear. Several studies demonstrated various oxidants to be capable of inducing PKG-Iα dimerization in order to mediate vasodilatation. Herein, we sought to investigate the role of nitrite on the PKG-Iα oxidation pathway using PKG wild-type (WT) and “redox-dead sensor” Cys42Ser knock-in (KI) mouse vasculature (conduit and resistance) under normoxic conditions. Furthermore, we assessed whether nitrite-mediated cardioprotection is dependent on active aldehyde dehydrogenase (ALDH2) (ALDH2 WT and knock-out (KO) mice) and if the Reperfusion Injury Salvage Kinase (RISK) pathway plays a role in this mechanism to reduce lipid peroxidation (4-HNE protein adducts).

We show two novel findings. Firstly, within the vasculature in normoxic conditions, the classical NO-sGC-cGMP pathway is involved in nitrite-mediated vasorelaxation in conduit murine vessels, but in resistance vessels PKG-Iα oxidation is involved. Secondly, nitrite acts as a pre-conditioning agent to protect the heart against myocardial ischaemia reperfusion injury by upregulating phosphorylation of RISK pathway mediators to activate ALDH2 pathway and decrease lipid peroxidation. These findings further support nitrite as a potential pharmacological agent for treating hypertension and myocardial injury.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):