Vascular Effects Of Hydrogen Sulfide

This book explores techniques for exploring hydrogen sulfide (H2S) and its effects on the vascular system through numerous experimental animal models and vascular preparations. Alterations of vascular H2S generation/signaling may be involved in the pathogenesis of systemic and pulmonary arterial hypertension, ischemic heart disease, ischemic stroke, preeclampsia, and erectile dysfunction, and H2S also serves as an attractive target for pharmacotherapy of cardiovascular diseases, as well as possible effects on cancer, wound healing, and diabetic retinopathy, among other pathologies. Written for the highly successful Methods in Molecular Biology series, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Vascular Effects of Hydrogen Sulfide: Methods and Protocols is an ideal aid for scientists working to extend our knowledge in this valuable and wide-ranging field of study.

Hydrogen sulfide (H2S) has emerged as an important gas signalling molecule in a series of organs/tissues, on the diseases of which it plays protective roles, such as proangiogenic effects in ischemic tissues, antiapoptotic effects in the cardiomyocytes, regularization of fatal arrhythmia in myocardial infarction, amelioration of inflammation in autoimmune diseases, modification of neuronal transmission, increase in sodium excretion from the kidney, and amelioration of insulin resistance, etc. This book focuses on the effect of hydrogen sulfide in cardiovascular system, immune system, nervous system, kidney, as well as on the metabolism of glucose and lipids and regulation of ion channels and so on. This book also provides the advances in the understanding of endogenous H2S metabolism and H2S protein targets, as well as H2S donors. It will benefit researchers in both academics and industry working on the underlying mechanism of H2S field and the future of translational medicine of H2S.

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-[gamma]-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.

This book puts hydrogen sulfide in context with other gaseous mediators such as nitric oxide and carbon monoxide, reviews the available mechanisms for its biosynthesis and describes its physiological and pathophysiological roles in a wide variety of disease states. Hydrogen sulfide has recently been discovered to be a naturally occurring gaseous mediator in the body. Over a relatively short period of time this evanescent gas has been revealed to play key roles in a range of physiological processes including control of blood vessel caliber and hence blood pressure and in the regulation of nerve function both in the brain and the periphery. Disorders concerning the biosynthesis or activity of hydrogen sulfide may also predispose the body to disease states such as inflammation, cardiovascular and neurological disorders. Interest in this novel gas has been high in recent years and many research groups worldwide have described its individual biological effects. Moreover, medicinal chemists are beginning to synthesize novel organic molecules that release this gas at defined rates with a view to exploiting these new compounds for therapeutic benefit.

In recent years it has become apparent that hydrogen sulphide (H2S) is an important biological mediator. In the vasculature, it produces complex responses: contraction in some blood vessels, relaxation in others, via multiple mechanisms. This thesis examined the relationship between H2S and oxygen in determining vascular responsiveness, and was conducted using porcine splenic and mesenteric arteries. Studies were also conducted using porcine splenic veins, since few studies have examined venous function. Additionally, studies were extended to the resistance vasculature by determining responses to a H2S donor in small arteries isolated from the rat mesentery. Porcine vessels were set up in an isometric tension recording system and rat small mesenteric arteries were set up in a pressure myograph. Vessels were pre-contracted and responses to the H2S donor, NaHS, were generated in the presence and absence of putative inhibitors, under either 95% O2:5% CO2, 95% air:5% CO2 or 95% N2:5% CO2 gassing conditions. Generally, in both porcine arteries and veins, when gassing with higher oxygen levels (95% O2:5% CO2 or 95% Air:5% CO2), NaHS induced contractile responses, whereas gassing with a lower oxygen level (95% N2:5% CO2), NaHS induced vasorelaxation. At higher O2 levels, removal of the endothelium or, the nitric oxide (NO) synthase inhibitor L-NAME, significantly attenuated contractile response in all porcine vessels. This suggests an interaction between endothelium-derived NO and NaHS, whereby the removal of the vasorelaxatory influence of NO resulted in contraction. In porcine arteries, relaxation at lower O2 levels was attenuated by glibenclamide, suggesting that NaHS activated KATP channels to cause relaxation. In porcine veins, removal of the endothelium or, L-NAME, abolished NaHS-induced relaxation, showing this relaxation occurred via the release of endothelium-derived NO. In rat mesenteric small arteries responses to NaHS did not change with different O2 levels and NaHS-induced vasodilatation that was abolished by desensitization of sensory nerves with capsaicin or the presence of BIBN 4096. These observations suggest NaHS-induced vasodilatation is mediated via release of CGRP from sensory nerves. Thus, responses to NaHS in large conduit arteries and veins, are sensitive to the prevailing level of O2 the tissue is exposed to. At more physiological levels of O2 the predominant response is a vasorelaxation, mediated by either, activation of KATP channels in arteries or, the release of NO in veins. In small arteries, the predominant response is a vasodilator response, involving the release of neuropeptides from sensory nerves. The predominance of a vasorelaxant/vasodilator response is consistent with the observation that mice which lack the capacity to generate endogenous H2S are hypertensive.

Due to population aging, calcific aortic valve disease (CAVD) has become the most common heart valve disease in Western countries. No therapies exist to slow this disease progression, and surgical valve replacement is the only effective treatment. Calcific Aortic Valve Disease covers the contemporary understanding of basic valve biology and the mechanisms of CAVD, provides novel insights into the genetics, proteomics, and metabolomics of CAVD, depicts new strategies in heart valve tissue engineering and regenerative medicine, and explores current treatment approaches. As we are on the verge of understanding the mechanisms of CAVD, we hope that this book will enable readers to comprehend our current knowledge and focus on the possibility of preventing disease progression in the future.

The endothelium, a monolayer of endothelial cells, constitutes the inner cellular lining of the blood vessels (arteries, veins and capillaries) and the lymphatic system, and therefore is in direct contact with the blood/lymph and the circulating cells. The endothelium is a major player in the control of blood fluidity, platelet aggregation and vascular tone, a major actor in the regulation of immunology, inflammation and angiogenesis, and an important metabolizing and an endocrine organ. Endothelial cells controls vascular tone, and thereby blood flow, by synthesizing and releasing relaxing and contracting factors such as nitric oxide, metabolites of arachidonic acid via the cyclooxygenases, lipoxygenases and cytochrome P450 pathways, various peptides (endothelin, urotensin, CNP, adrenomedullin, etc.), adenosine, purines, reactive oxygen species and so on. Additionally, endothelial ectoenzymes are required steps in the generation of vasoactive hormones such as angiotensin II. An endothelial dysfunction linked to an imbalance in the synthesis and/or the release of these various endothelial factors may explain the initiation of cardiovascular pathologies (from hypertension to atherosclerosis) or their development and perpetuation. Table of Contents: Introduction / Multiple Functions of the Endothelial Cells / Calcium Signaling in Vascular Cells and Cell-to-Cell Communications / Endothelium-Dependent Regulation of Vascular Tone / Conclusion / References

Aorta CSE and CBS mRNA expression was higher with CR. Hydrogen sulfide production was also higher with CR in aorta and liver. I conclude that in rat aorta the triphasic responses to hypoxia and H2S are mediated by different mechanisms, hydrogen sulfide up-regulates eNOS/NO production through an Akt-dependent mechanism, and the increased sensitivity to hydrogen sulfide and increased protein expression of CSE and CBS with age in aorta point to a drop in hydrogen sulfide bioavailability, while CR maintains CSE/CBS function. These studies reveal novel, age-sensitive mechanisms of hydrogen sulfide action to regulate vascular tone. They also illustrate the benefit of CR on the hydrogen sulfide signaling system. This is quite timely, given the emerging roles of hydrogen sulfide in cardiovascular pathologies.

Showcasing the recent progresses of the field, Cyclic Nucleotide Signaling covers the major tools and methodologies used in various areas of research. The majority of the chapters are protocol oriented, with the goal of providing clear directions for laboratory use. Students and investigators new to the field will find this book particularly informative, as will scientists already actively researching nucleotide signaling.

This is the premier, single-source reference on redox biochemistry, a rapidly emerging field. This reference presents the basic principles and includes detailed chapters focusing on various aspects of five primary areas of redox biochemistry: antioxidant molecules and redox cofactors; antioxidant enzymes; redox regulation of physiological processes; pathological processes related to redox; and specialized methods. This is a go-to resource for professionals in pharmaceuticals, medicine, immunology, nutrition, and environmental fields and an excellent text for upper-level students.