scholarly journals Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research

2011 ◽  
Vol 300 (1) ◽  
pp. H13-H26 ◽  
Author(s):  
Richard S. Beard ◽  
Shawn E. Bearden
Keyword(s):  
Hydrogen Sulfide ◽  
Animal Studies ◽  
Disease Risk ◽  
Vascular Complications ◽  
Disease Risk Factor ◽  
Positive Effects ◽  
Relative Paucity ◽  
Transsulfuration Pathway ◽  
Rate Limiting

Homocysteine (Hcy), a cardiovascular and neurovascular disease risk factor, is converted to hydrogen sulfide (H2S) through the transsulfuration pathway. H2S has attracted considerable attention in recent years for many positive effects on vascular health and homeostasis. Cystathionine β-synthase (CBS) is the first, and rate-limiting, enzyme in the transsulfuration pathway. Mutations in the CBS gene decrease enzymatic activity, which increases the plasma Hcy concentration, a condition called hyperhomocysteinemia (HHcy). Animal models of CBS deficiency have provided invaluable insights into the pathological effects of transsulfuration impairment and of both mild and severe HHcy. However, studies have also highlighted the complexity of HHcy and the need to explore the specific details of Hcy metabolism in addition to Hcy levels per se. There has been a relative paucity of work addressing the dysfunctional H2S production in CBS deficiency that may contribute to, or even create, HHcy-associated pathologies. Experiments using CBS knockout mice, both homozygous (−/−) and heterozygous (+/−), have provided 15 years of new knowledge and are the focus of this review. These murine models present the opportunity to study a specific mechanism for HHcy that matches one of the etiologies in many human patients. Therefore, the goal of this review was to integrate and highlight the critical information gained thus far from models of CBS deficiency and draw attention to critical gaps in knowledge, with particular emphasis on the modulation of H2S metabolism. We include findings from human and animal studies to identify important opportunities for future investigation that should be aimed at generating new basic and clinical understanding of the role of CBS and transsulfuration in cardiovascular and neurovascular disease.

scholarly journals Extracellular transsulfuration generates hydrogen sulfide from homocysteine and protects endothelium from redox stress

2010 ◽  
Vol 299 (5) ◽  
pp. H1568-H1576 ◽  
Author(s):  
Shawn E. Bearden ◽  
Richard S. Beard ◽  
Jean C. Pfau
Keyword(s):  
Hydrogen Sulfide ◽  
Cell Function ◽  
Disease Risk ◽  
Clinical Diagnostics ◽  
Serum Starvation ◽  
Redox Stress ◽  
Disease Risk Factor ◽  
Homocysteine Concentration ◽  
Transsulfuration Pathway ◽  
Reoxygenation Injury

Homocysteine, a cardiovascular and neurocognitive disease risk factor, is converted to hydrogen sulfide, a cardiovascular and neuronal protectant, through the transsulfuration pathway. Given the damaging effects of free homocysteine in the blood and the importance of blood homocysteine concentration as a prognosticator of disease, we tested the hypotheses that the blood itself regulates homocysteine-hydrogen sulfide metabolism through transsulfuration and that transsulfuration capacity and hydrogen sulfide availability protect the endothelium from redox stress. Here we show that the transsulfuration enzymes, cystathionine β-synthase and cystathionine γ-lyase, are secreted by microvascular endothelial cells and hepatocytes, circulate as members of the plasma proteome, and actively produce hydrogen sulfide from homocysteine in human blood. We further demonstrate that extracellular transsulfuration regulates cell function when the endothelium is challenged with homocysteine and that hydrogen sulfide protects the endothelium from serum starvation and from hypoxia-reoxygenation injury. These novel findings uncover a unique set of opportunities to explore innovative clinical diagnostics and therapeutic strategies in the approach to homocysteine-related conditions such as atherosclerosis, thrombosis, and dementia.

scholarly journals Hydrogen Sulfide: A Therapeutic Option in Systemic Sclerosis

2018 ◽  
Vol 19 (12) ◽  
pp. 4121 ◽  
Author(s):  
Amaal Abdulle ◽  
Harry van Goor ◽  
Douwe Mulder
Keyword(s):  
Hydrogen Sulfide ◽  
Systemic Sclerosis ◽  
Animal Studies ◽  
Therapeutic Option ◽  
Multiple Organ ◽  
Current Data ◽  
Organ Systems ◽  
Transsulfuration Pathway ◽  
Exact Etiology ◽  
Vascular Physiology

Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related complications. In addition to the well-known detrimental properties of reactive oxygen species (ROS), gasotransmitters (e.g., nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)) are also thought to play an important role in SSc. Accordingly, the diverse physiologic actions of NO and CO and their role in SSc have been previously studied. Recently, multiple studies have also shown the importance of the third gasotransmitter H2S in both vascular physiology and pathophysiology. Interestingly, homocysteine (which is converted into H2S through the transsulfuration pathway) is often found to be elevated in SSc patients; suggesting defects in the transsulfuration pathway. Hydrogen sulfide, which is known to have several effects, including a strong antioxidant and vasodilator effect, could potentially play a prominent role in the initiation and progression of vasculopathy. A better understanding of the actions of gasotransmitters, like H2S, in the development of SSc-related vasculopathy, could help to create early interventions to attenuate the disease course. This paper will review the role of H2S in vascular (patho-)physiology and potential disturbances in SSc. Moreover, current data from experimental animal studies will be reviewed. Lastly, we will evaluate potential interventional strategies.

scholarly journals Flavonoid intake and the risk of ischaemic stroke and CVD mortality in middle-aged Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study

2008 ◽  
Vol 100 (4) ◽  
pp. 890-895 ◽  
Author(s):  
Jaakko Mursu ◽  
Sari Voutilainen ◽  
Tarja Nurmi ◽  
Tomi-Pekka Tuomainen ◽  
Sudhir Kurl ◽  
...  
Keyword(s):  
Risk Factor ◽  
Heart Disease ◽  
Ischaemic Stroke ◽  
Disease Risk ◽  
Disease Risk Factor ◽  
Risk Factor Study ◽  
Factor Study ◽  
Heart Disease Risk ◽  
Cvd Mortality

The role of flavonoids in CVD, especially in strokes, is unclear. Our aim was to study the role of flavonoids in CVD. We studied the association between the intakes of five subclasses (flavonols, flavones, flavanones, flavan-3-ols and anthocyanidins), a total of twenty-six flavonoids, on the risk of ischaemic stroke and CVD mortality. The study population consisted of 1950 eastern Finnish men aged 42–60 years free of prior CHD or stroke as part of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. During an average follow-up time of 15·2 years, 102 ischaemic strokes and 153 CVD deaths occurred. In the Cox proportional hazards model adjusted for age and examination years, BMI, systolic blood pressure, hypertension medication, serum HDL- and LDL-cholesterol, serum TAG, maximal oxygen uptake, smoking, family history of CVD, diabetes, alcohol intake, energy-adjusted intake of folate, vitamin E, total fat and saturated fat intake (percentage of energy), men in the highest quartile of flavonol and flavan-3-ol intakes had a relative risk of 0·55 (95 % CI 0·31, 0·99) and 0·59 (95 % CI 0·30, 1·14) for ischaemic stroke, respectively, as compared with the lowest quartile. After multivariate adjustment, the relative risk for CVD death in the highest quartile of flavanone and flavone intakes were 0·54 (95 % CI 0·32, 0·92) and 0·65 (95 % CI 0·40, 1·05), respectively. The present results suggest that high intakes of flavonoids may be associated with decreased risk of ischaemic stroke and possibly with reduced CVD mortality.

scholarly journals Phosphoglycerate Dehydrogenase: Potential Therapeutic Target and Putative Metabolic Oncogene

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Cheryl K. Zogg
Keyword(s):  
Therapeutic Target ◽  
Animal Studies ◽  
Potential Therapeutic Target ◽  
Subsequent Work ◽  
Glycolytic Intermediate ◽  
Rate Limiting Step ◽  
Phosphoglycerate Dehydrogenase ◽  
Altered Metabolism ◽  
Rate Limiting

Exemplified by cancer cells’ preference for glycolysis, for example, the Warburg effect, altered metabolism in tumorigenesis has emerged as an important aspect of cancer in the past 10–20 years. Whether due to changes in regulatory tumor suppressors/oncogenes or by acting as metabolic oncogenes themselves, enzymes involved in the complex network of metabolic pathways are being studied to understand their role and assess their utility as therapeutic targets. Conversion of glycolytic intermediate 3-phosphoglycerate into phosphohydroxypyruvate by the enzyme phosphoglycerate dehydrogenase (PHGDH)—a rate-limiting step in the conversion of 3-phosphoglycerate to serine—represents one such mechanism. Forgotten since classic animal studies in the 1980s, the role of PHGDH as a potential therapeutic target and putative metabolic oncogene has recently reemerged following publication of two prominent papers near-simultaneously in 2011. Since that time, numerous studies and a host of metabolic explanations have been put forward in an attempt to understand the results observed. In this paper, I review the historic progression of our understanding of the role of PHGDH in cancer from the early work by Snell through its reemergence and rise to prominence, culminating in an assessment of subsequent work and what it means for the future of PHGDH.

scholarly journals The Role of Oxytocin and the Effect of Stress During Childbirth: Neurobiological Basics and Implications for Mother and Child

2021 ◽  
Vol 12 ◽  
Author(s):  
Michael H. Walter ◽  
Harald Abele ◽  
Claudia F. Plappert
Keyword(s):  
Animal Studies ◽  
Infant Health ◽  
Negative Effects ◽  
Positive Effects ◽  
Current State ◽  
Maternal And Infant Health ◽  
Maternal Brain ◽  
Mother And Child ◽  
Controlling Processes

The neuropeptide oxytocin acts as a hormone and a neuromodulator, influencing a multitude of human social behaviors, including reproduction. During childbirth and the postpartum period, it plays a key role in regulating and controlling processes that ensure a safe birth and the health of mother and child. Especially the onset of labor, the progress of labor and initial breastfeeding are mediated by oxytocin. In the maternal brain it controls the initiation of the mother–infant bond and the mother’s emotional responses towards her child. In this review we summarize the current state of knowledge about the role of oxytocin during the different aspects and mechanisms of human childbirth, combining research from human and animal studies. Physiological and psychological stress during childbirth and lactation can have negative effects on the progress of labor, breastfeeding and bonding. We discuss how maternity caregivers can support the positive effects of oxytocin and minimize the effects of stress. Furthermore, we highlight aspects of the basic neurobiological principles and connections where further research is needed to improve our understanding of the regulation and the effects of oxytocin to support maternal and infant health.

scholarly journals Methionine Nutrition and Metabolism: Insights from Animal Studies to Inform Human Nutrition

2020 ◽  
Vol 150 (Supplement_1) ◽  
pp. 2518S-2523S ◽  
Author(s):  
Rajavel Elango
Keyword(s):  
Animal Studies ◽  
Animal Feed ◽  
Lessons Learned ◽  
The Body ◽  
Methyl Donors ◽  
Transsulfuration Pathway ◽  
Indispensable Amino Acids ◽  
Rate Limiting ◽  
Plant Sources

ABSTRACT Methionine is a nutritionally indispensable amino acid, and is unique among indispensable amino acids due to its sulfur atom. Methionine is involved in cysteine synthesis via the transsulfuration pathway, which is rate limiting for the key antioxidant molecule, glutathione. Methionine is also the primary methyl donor in the body through S-adenosylmethionine via the transmethylation pathway, which is involved in the synthesis of several key metabolites including creatine and phosphatidylcholine. Methionine can also be remethylated from homocysteine, in the presence of betaine via choline and/or folate. Thus methionine demands from a dietary perspective are regulated not only by the presence of cysteine in the body, but also by the demands in vivo for the various metabolites formed from it, and also by the presence of these compounds in foods. Indeed, methionine, cysteine, and the various methyl donors/acceptors vary in human foods, and thus regulate methionine availability, especially under conditions of growth and development. Much of our understanding of methionine nutrition and metabolism arises from experiments in animal models. This is because most animal feed formulations are plant-based and plant sources are relatively low in methionine and cysteine amounts. Thus, this brief review will touch on some broad aspects of human methionine nutrition, including requirements in different life stages, disease, and bioavailability, with some examples from the insights/lessons learned from experiments initially conducted in animals.

scholarly journals Defining the role of the Alzheimer disease risk factor CD2AP in brain vascular function

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Milene Vandal ◽  
Colin Gunn ◽  
Philippe Bourassa ◽  
Adam Institoris ◽  
Steven Seungjae Shin ◽  
...  
Keyword(s):  
Risk Factor ◽  
Alzheimer Disease ◽  
Vascular Function ◽  
Disease Risk ◽  
Disease Risk Factor

Bisphenol F exposure in adolescent heterogeneous stock (HS) rats affects growth and adiposity

2021 ◽  
Author(s):  
Valerie A Wagner ◽  
Karen C Clark ◽  
Leslie Carrillo-Sáenz ◽  
Katie A Holl ◽  
Miriam Velez-Bermudez ◽  
...  
Keyword(s):  
Disease Risk ◽  
Consumer Products ◽  
Model Organisms ◽  
Cardiometabolic Disease ◽  
Trait Variation ◽  
Disease Risk Factor ◽  
Heterogeneous Stock ◽  
Bisphenol F ◽  
Metabolizing Enzyme

Abstract Bisphenol F (BPF) is increasingly substituting bisphenol A (BPA) in manufacturing polycarbonates and consumer products. The cardiometabolic effects of BPF in either humans or model organisms are not clear, and no studies to date have investigated the role of genetic background on susceptibility to BPF-induced cardiometabolic traits. The primary goal of this project was to determine if BPF exposure influences growth and adiposity in male N: NIH Heterogeneous Stock (HS) rats, a genetically heterogeneous population. Littermate pairs of male HS rats were randomly exposed to either vehicle (0.1% Ethanol) or 1.125 µg/ml BPF in 0.1% Ethanol for five weeks in drinking water starting at three weeks-of-age. Water consumption and body weight was measured weekly, body composition was determined using nuclear magnetic resonance (NMR), urine and feces were collected in metabolic cages, and blood and tissues were collected at the end of the study. BPF-exposed rats showed significantly increased body growth and abdominal adiposity, risk factors for cardiometabolic disease. Urine output was increased in BPF-exposed rats, driving a trend in increased creatinine clearance. We also report the first relationship between a bisphenol metabolizing enzyme and a bisphenol-induced phenotype. Preliminary heritability estimates of significant phenotypes suggest that BPF exposure may alter trait variation. These findings support BPF exposure as a cardiometabolic disease risk factor and indicate that the HS rat will be a useful model for dissecting gene by BPF interactions on metabolic health.

Testosterone supplementation in aging men and women: possible impact on cardiovascular-renal disease

2005 ◽  
Vol 289 (5) ◽  
pp. F941-F948 ◽  
Author(s):  
Jane F. Reckelhoff ◽  
Licy L. Yanes ◽  
Radu Iliescu ◽  
Lourdes A. Fortepiani ◽  
Joey P. Granger
Keyword(s):  
Renal Disease ◽  
Animal Studies ◽  
De Novo ◽  
Disease Risk ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Men And Women ◽  
Aging Men

Treatment of aging men and women with testosterone supplements is increasing. The supplements are given to postmenopausal women mainly to improve their libido and to aging men to improve muscle mass and bone strength, to improve libido and quality of life, to prevent and treat osteoporosis, and, with the phosphodiesterase-5 inhibitors, such as sildenafil, to treat erectile dysfunction. The increased use of testosterone supplements in aging individuals has occurred despite the fact that there have been no rigorous clinical trials examining the effects of chronic testosterone on the cardiovascular-renal disease risk. Studies in humans and animals have suggested that androgens can increase blood pressure and compromise renal function. Androgens have been shown to increase tubular sodium and water reabsorption and activate various vasoconstrictor systems in the kidney, such as the renin-angiotensin system and endothelin. There is also evidence that androgens may increase oxidative stress. Furthermore, the kidney contains the enzymes necessary to produce androgens de novo. This review presents an overview of the data from human and animal studies in which the role of androgens in promoting renal and cardiovascular diseases has been investigated.

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