monash_81621.pdf (1.71 MB)
Download file

The role of hydrogen sulfide in the cardiovascular system

Download (1.71 MB)
thesis
posted on 31.01.2017, 05:30 authored by Al-Magableh, Mohammad
Hydrogen sulfide , commonly known as “rotten egg gas”, is now considered an endogenously derived gaseous mediator, akin to nitric oxide . It is generated in vascular cells primarily from L-cysteine by the enzyme cystathionine-γ-lyase and is implicated in the regulation of the cardiovascular system, where H2S causes vasorelaxation. Other reports show that H2S has anti-inflammatory and anti-oxidant effects that may elicit protection from oxidative stress. Many reports have studied the mechanism of H2S-induced vasorelaxation but none have fully elucidated it, thus this was the first aim of the study. Using myograph techniques, it was found that the activation of KATP, KV, KCa, KIR channels and inhibition of Ca2+ channels were all implicated in the vasorelaxation response to H2S in conduit and resistance-like arteries. Additionally, the endogenous vascular production of H2S was examined, using a biochemical enzyme assay technique in conjunction with myography. A modest, reproducible contribution of the L-cysteine/CSE/H2S pathway to overall vasoregulation was revealed. Importantly, immunohistochemistry studies showed that CSE was found mainly in the endothelial cells of blood vessels. Furthermore, inhibition of CSE impaired endothelium-mediated vasorelaxation responses and increased basal vascular tone. These data imply a role for H2S in the modulation of the vascular system. The anti-oxidant effects of H2S have been highlighted by many reports. The next aim of the study was to examine the anti-oxidant effects of H2S in the vasculature. Using lucigenin-enhanced chemiluminescence, it was demonstrated that H2S can scavenge superoxide anions in a physiological solution and furthermore, H2S can inhibit superoxide anion formation in isolated blood vessels by inhibiting NADPH oxidase. An extension of this study showed that H2S can also protect endothelial function from acute oxidative stress in vitro in a blood vessel bioassay preparation. Having found an in vitro vasoprotective effect of H2S, the anti-oxidant effects of H2S were tested in vivo. In an animal model of oxidative stress and hypertension elicited by chronic angiotensin II treatment, concomitant H2S treatment for two weeks (daily intraperitoneal injection of NaHS) reduced blood pressure, improved endothelial function and decreased superoxide production induced by AngII in these animals. These data extend the in vitro findings of this study and confirm that the anti-oxidant and vasoprotective effect also occurs in vivo. Overall, the aims of the thesis were to elucidate the mechanism of H2S-mediated vasorelaxation, examine the contribution of endogenous H2S to vascular regulation and examine the potential vasoprotective effects of H2S. The results show that H2S is endogenously produced and causes vasorelaxation via K+ and Ca2+ channel mediated pathways. H2S plays a role in endothelium-mediated vasorelaxation and has important vascular anti-oxidant effects in vitro, anti-oxidant and antihypertensive properties in vivo. These data suggest that H2S may be an important target for pharmacotherapy in cardiovascular diseases involving oxidative stress and blood vessel dysfunction.

History

Principal supervisor

Joanne Hart

Additional supervisor 1

Barbara Kemp-Harper

Year of Award

2011

Department, School or Centre

Pharmacology

Campus location

Australia

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Medicine Nursing and Health Sciences