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The Role of Asprosin in the Regulation and Mechanisms of Oxygen Transport in the Blood and the Gas Transmitter System in Men with Different Body Mass Index
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Humans elicit a robust series of physiological responses to maintain adequate oxygen delivery during hypoxia, including a transient reduction in hemoglobin-oxygen (Hb-O2) affinity. However, high Hb-O2 affinity has been identified as a beneficial adaptation in several species that have been exposed to high altitude for generations. The observed differences in Hb-O2 affinity between humans and species adapted to high altitude pose a central question: is higher or lower Hb-O2 affinity in humans more advantageous when O2 availability is limited? Humans with genetic mutations in hemoglobin structure resulting in high Hb-O2 affinity have shown attenuated cardiorespiratory adjustments during hypoxia both at rest and during exercise, providing unique insight into this central question. Therefore, the purpose of this review is to examine the influence of high Hb-O2 affinity during hypoxia through comparison of cardiovascular and respiratory adjustments elicited by humans with high Hb-O2 affinity compared to those with normal Hb-O2 affinity.
Aim To study blood adipokines spectrum in people aged 25–44 years with early ischemic heart disease (IHD), including that associated with abdominal obesity (AO).
Material and methods A cross-sectional study was performed on a random sample of the population aged 25–44 years in Novosibirsk. 1457 subjects (653 men, 804 women) were evaluated. This study included 123 people divided into four study subgroups: subgroup 1, with IHD associated with AO (n=24); subgroup 2, with IHD and without AO (n=25); subgroup 3, without IHD and with AO (n=44); and subgroup 4, without either IHD or AO (n=30). Concentrations of serum adipokines were measured simultaneously by multiplex assay with a Luminex MAGPIX flow fluorometer and by immune enzyme assay with a MULTISCAN analyzer.
Results Subjects with early IHD had lower blood concentrations of adipsin and visfatin than subjects without IHD. Subjects with early IHD associated with AO had higher blood concentrations of adipsin, plasminogen activator inhibitor-1, and leptin and lower concentrations of monocyte chemoattractant protein-1 (MCP-1) and visfatin compared to subjects with early IHD and without AO. The multivariate logistic regression analysis showed that lower blood concentrations of MCP-1 were associated with a likelihood of early IHD.
Conclusion In young people aged 25–44 years, lower blood concentrations of MCP-1 were associated with a likelihood of early IHD, including that associated with AO.
The review discusses published data on the effect of hydrogen sulfide on the functioning of the cardiovascular system. Hydrogen sulfide has become the third gas molecule, along with NO and CO, which was classified as gasotransmitters – signaling molecules, a unique feature of which is their ability to easily penetrate the cell membrane due to their good solubility in lipids. Signal transduction with the participation of gasotransmitters significantly differs from classical concepts – there is no need for either special membrane receptors or transport systems, gasotransmitters realize their effect practically in the zone of their biosynthesis, which makes such regulation fast and accurate. In the cardiovascular system, hydrogen sulfide has shown a pronounced cardioprotective effect, especially pronounced in conditions of hypertension and myocardial ischemia. Along with NO, hydrogen sulfide is the most important regulator of vascular tone, while it affects both the properties of the endothelium and regulates the contractility of vascular smooth muscle cells. The role of H 2 S in the pathogenesis of arterial hypertension and the therapeutic potential of this gasotransmitter and its derivatives in arterial hypertension treatment both in animal models and in clinical studies have been demonstrated. Experimental data confirming the participation of hydrogen sulfide in the processes of angiogenesis and in the pathogenesis of atherosclerosis were published. For the cardiovascular system, the main function of which is the oxygen supply to organs and tissues, the ability of this gasotransmitter to influence the blood system and act as an oxygen sensor seems to be important. Hydrogen sulfide affects the functional properties of platelets, thrombus stability and microvascular thrombolysis; there is experimental evidence of the effect of H 2 S on the microrheological properties of erythrocytes and the process of erythrogenesis. And although the mechanisms of the effect of hydrogen sulfide have not yet been sufficiently studied, there is evidence that all gasotransmitters are in close interaction and their joint action gives a synergistic effect.
Hydrogen sulfide (H2S) is naturally synthesized in a wide range of mammalian tissues. Whether H2S is involved in the regulation of erythrocyte functions remains unknown. Using mice with a genetic deficiency in a H2S natural synthesis enzyme cystathionine-γ-lyase (CSE) and high-throughput metabolomic profiling, we found that levels of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), an erythroid-specific metabolite negatively regulating hemoglobin- (Hb-) oxygen (O2) binding affinity, were increased in CSE knockout (Cse-/-) mice under normoxia. Consistently, the 50% oxygen saturation (P50) value was increased in erythrocytes of Cse-/- mice. These effects were reversed by treatment with H2S donor GYY4137. In the models of cultured mouse and human erythrocytes, we found that H2S directly acts on erythrocytes to decrease 2,3-BPG production, thereby enhancing Hb-O2 binding affinity. Mouse genetic studies showed that H2S produced by peripheral tissues has a tonic inhibitory effect on 2,3-BPG production and consequently maintains Hb-O2 binding affinity in erythrocytes. We further revealed that H2S promotes Hb release from the membrane to the cytosol and consequently enhances bisphosphoglycerate mutase (BPGM) anchoring to the membrane. These processes might be associated with S-sulfhydration of Hb. Moreover, hypoxia decreased the circulatory H2S level and increased the erythrocyte 2,3-BPG content in mice, which could be reversed by GYY4137 treatment. Altogether, our study revealed a novel signaling pathway that regulates oxygen-carrying capacity in erythrocytes and highlights a previously unrecognized role of H2S in erythrocyte 2,3-BPG production.
Asprosin, a novel glucogenic adipokine, is encoded by two exons (exon 65 and exon 66) of the gene Fibrillin 1 (FBN1) and mainly synthesized and released by white adipose tissue during fasting. Asprosin plays a complex role in the central nervous system (CNS), peripheral tissues, and organs. It is involved in appetite, glucose metabolism, insulin resistance (IR), cell apoptosis, etc. In this review, we will summarize the newly discovered roles of asprosin in metabolic diseases including diabetes, obesity, polycystic ovarian syndrome (PCOS), and cardiovascular disease (CVD), which may contribute to future clinical diagnosis and treatment.
Obesity, typically quantified in terms of Body Mass Index (BMI) exceeding threshold values, is considered a leading cause of premature death worldwide. For given body size (BMI), it is recognized that risk is also affected by body shape, particularly as a marker of abdominal fat deposits. Waist circumference (WC) is used as a risk indicator supplementary to BMI, but the high correlation of WC with BMI makes it hard to isolate the added value of WC.
We considered a USA population sample of 14,105 non-pregnant adults (age ≥ 18) from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 with follow-up for mortality averaging 5 yr (828 deaths). We developed A Body Shape Index (ABSI) based on WC adjusted for height and weight: ABSI ≡ WC/(BMI(2/3)height(1/2)). ABSI had little correlation with height, weight, or BMI. Death rates increased approximately exponentially with above average baseline ABSI (overall regression coefficient of +33% per standard deviation of ABSI [95% confidence interval: +20%-+48%), whereas elevated death rates were found for both high and low values of BMI and WC. 22% (8%-41%) of the population mortality hazard was attributable to high ABSI, compared to 15% (3%-30%) for BMI and 15% (4%-29%) for WC. The association of death rate with ABSI held even when adjusted for other known risk factors including smoking, diabetes, blood pressure, and serum cholesterol. ABSI correlation with mortality hazard held across the range of age, sex, and BMI, and for both white and black ethnicities (but not for Mexican ethnicity), and was not weakened by excluding deaths from the first 3 yr of follow-up.
Body shape, as measured by ABSI, appears to be a substantial risk factor for premature mortality in the general population derivable from basic clinical measurements. ABSI expresses the excess risk from high WC in a convenient form that is complementary to BMI and to other known risk factors.
Metabolic syndrome includes the following symptoms: obesity, hyperlipidemia, hypertension, insulin resistance, and cardiovascular disease. The purpose of this review is to elucidate the role of adipokines in the regulation of the L-arginine-NO-synthas-NO signaling pathway in the pathogenesis of metabolic syndrome. The main questions raised in the review are: how adipokine secretion changes, how the level of their receptors is regulated, and which signaling pathways are involved in the transmission of adipokine signals when coupled to the L-arginine-NO-synthase-NO signaling cascade. Adipokines are peptide hormones that transmit a signal from adipose tissue to targets in the brain, blood vessels, liver, pancreas, muscles, and other tissues. Some adipokines have anti-inflammatory and insulin-sensitive effects: adiponectin, omentin, adipolin, chemerin, progranulin. Others have the negative inflammatory effect in the development ofmetabolic syndrome: visfatin, vaspin, apelin. Adipokines primarily regulate the expression and activity of endothelial NO-synthase. They either activate an enzyme involving 5-AMP protein kinase or Akt kinase, increasing its activity and synthesis of NO in the tissues of healthy patients: adiponectin, adipolin, omentin, or inhibit the activity of eNOS, which leads to a decrease in NO-synthase and suppression of mRNA bioavailability: vaspin, visfatin, apelin in metabolic syndrome, and a decrease in its activity leads to dissociation and endothelial dysfunction. It should be noted that the bioavailability of NO formed by NO-synthase is affected at many levels, including: the expression ofNO-synthase mRNA and its protein; the concentration of L-arginine; the level of cofactors of the reaction; and to detect the maximum activity of endothelial NO-synthase, dimerization of the enzyme is required, posttranslational modifications are important, in particular, phosphorylation of endothelial NO-synthase by serine 1177 with the participation of 5-AMP protein kinase, Akt kinase and other kinases. It should be noted that the participation of adiponectin, omentin, and kemerin in the regulation of the L-arginine-NO-synthase-NO cascade in metabolic syndrom opens up certain opportunities for the development of new approaches for the correction of disorders observed in this disease. The review analyzes the results of research searching in PubMed databases, starting from 2001 and up to 2020 using keywords and adipokine names, more than half of the references of the last 5 years.
BACKGROUND: The global COVID-19 pandemic, caused by the SARS-CoV-2 virus, has created great problems in healthcare systems throughout the world. Although, just like other respiratory tract viral infections, it is a disease with pathophysiological processes associated in general with cytokine production, inflammation, cell death, and redox imbalance or oxidative stress, very little is known about the pathology. Also; In recent studies, the effect of asprosin, which has an important and complex role on metabolism, on COVID-19 is unknown. The aim of this study is determining the level of asprosin, a new hormone that has the potential to affect many metabolic pathways such as glucose metabolism, in COVID-19 patients. In addition, it is to determine whether asprosin is associated with oxidative stress in COVID-19 patients.
METHODS: Blood samples were taken from 30 patients diagnosed with COVID-19 confirmed with RT-PCR test, and 30 healthy control subjects. The serum asprosin level was analyzed with ELISA, and Total Antioxidant Status (TAS) and Total Oxidant Status (TOS) levels with colorimetric analysis.
RESULTS: The asprosin and TAS levels were determined to be statistically significantly decreased in the COVID-19 patients, and the TOS and OSI levels were significantly increased.
CONCLUSIONS: It can be thought that a decrease in asprosin level in COVID-19 patients causes a decrease in metabolic activity, prevents sufficient energy production in patients, and therefore oxidative stress increases in patients.
We studied the effects of melatonin on the oxygen transport in blood and prooxidant−antioxidant balance in males aged from 18 to 21 years in submaximal physical exercise. The subjects received 3 mg of melatonin once a day for two months. As a result of melatonin administration, we observed a shift of oxyhemoglobin dissociation to the right, which results in reduced manifestation of oxidative stress after physical exercise. We found that the increased level of gas transmitters (nitrogen monoxide and hydrogen sulfide) after melatonin administration can influence oxygen transport in blood and prooxidant–antioxidant balance in exercise.
Background:
Nitric oxide (NO) is involved in formation of oxygen transport function of blood and oxygen transport in tissues by means of interaction with haemoglobin. Endothelial nitric oxide synthase gene G894T polymorphism affects the expression and the activity of the NO synthase enzyme. The influence of this polymorphism on the formation of oxygen-dependent processes in the body has not been completely investigated.
Objective:
To evaluate the associations between G894T polymorphism of the endothelial nitric oxide synthase gene and the condition of oxygen transport function of blood in healthy male volunteers.
Methods:
The study subjects were healthy young males aged 18-24 years (n = 165). The blood was drawn from the cubital vein at rest after 12 h following the last food intake. G984T polymorphism and the blood oxygen indices pO2, CvO2, SO2, pH, р50stand (the temperature was 37°С, рН = 7.4, рСО2 = 40 mm Hg) and р50act (actual temperature, рН and рСО2), etc. were determined.
Results:
In persons with the TT-genotype, the oxygen content in venous blood was 48.7% (q = 0.019) lower compared to subjects with the GT-genotype and 49.4% (q = 0.019) lower compared to subjects with the GG-genotype. The saturation of blood in carriers of the TT-genotype was 32.4% (q = 0.021) and 35.9% (q = 0.019) lower as opposed to subjects with the GT-genotype and the GG-genotype, respectively. In blood of subjects with the TT-genotype, the oxygen tension was 26.1% (q = 0.019) lower as compared to subjects with the GT-genotype and 27.4% (q = 0.019) lower as opposed to the GG-genotype. In turn, volunteers having a common allele in their genotype (GG + GT) demonstrated oxygen tension to be 26.7% (q = 0.019) higher compared to subjects with the TT-genotype. The blood pH values of the subjects having the recessive genotype were 0.022 units lower compared to the GG (q = 0.044) and GT (q = 0.042) genotypes. In volunteers with the TT-genotype, the p50stand parameter was 5.8% (q = 0.027) lower compared to subjects with the GT-genotype and 6.8% (q = 0.019) lower compared to volunteers with the GG-genotype. In persons with two T-alleles in their genotype, p50act was 5.4% (q = 0.019) lower compared to subjects with the GT-genotype and 6.4% (q = 0.019) lower compared to persons with the GG-genotype.
Conclusion:
The T-allele of G894T polymorphism is associated with low values for oxygen content, oxygen tension, acidic pH shift and increased haemoglobin affinity for oxygen under standard and real conditions. The presence of a minor allele in G894T polymorphism of the NOS3 gene contributes to formation of oxygen transport function of blood.
Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glycogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.
The liver is likely exposed to high levels of hydrogen sulfide (H2S) from endogenous hepatic synthesis and exogenous sources from the gastrointestinal tract. Little is known about the consequence of H2S exposure on the liver or hepatic regulation of H2S levels. We hypothesized that the liver has a high capacity to metabolize H2S and that H2S oxidation is decreased during sepsis, a condition in which hepatic O2 is limited and H2S synthesis is increased. Using a nonrecirculating isolated and perfused liver system, we demonstrated rapid hepatic H2S metabolism up to an infusion concentration of 200' μM H2S. Hydrogen sulfide metabolism was associated with an increase in O2 consumption from a baseline 96.7 ± 7.6 μmol O2/min/kg to 109 ± 7.4 μmol O2/min/kg at an infusion concentration of 150 μM H2S (P < 0.001). Removal of O2 from the perfusate decreased H2S clearance from a maximal 97% to only 23%. Livers isolated from rats subjected to cecal ligation and puncture (CLP) did not differ significantly from control livers in their capacity to metabolize H2S, suggesting that H2S oxidation remains a priority during sepsis. To test whether H2S induces O2 consumption in vivo, intravital microscopy was utilized to monitor the oxygen content in the hepatic microenvironment. Infusion of H2S increased the NADH/NAD+ ratio (645 gray-scale-unit increase, P = 0.035) and decreased hepatic O2 availability visualized with Ru(Phen)3(2+) (439 gray-scale-unit increase, P = 0.040). We conclude that the liver has a high hepatic capacity for H2S metabolism. Moreover, H2S oxidation consumes available oxygen and may exacerbate the tissue hypoxia associated with sepsis.
Nitric oxide (NO) methodology is a complex and often confusing science and the focus of many debates and discussion concerning NO biochemistry. NO is involved in many physiological processes including regulation of blood pressure, immune response, and neural communication. Therefore its accurate detection and quantification are critical to understanding health and disease. Due to the extremely short physiological half-life of this gaseous free radical, alternative strategies for the detection of reaction products of NO biochemistry have been developed. The quantification of NO metabolites in biological samples provides valuable information with regard to in vivo NO production, bioavailability, and metabolism. Simply sampling a single compartment such as blood or plasma may not always provide an accurate assessment of whole body NO status, particularly in tissues. Therefore, extrapolation of plasma or blood NO status to specific tissues of interest is no longer a valid approach. As a result, methods continue to be developed and validated which allow the detection and quantification of NO and NO-related products/metabolites in multiple compartments of experimental animals in vivo. The methods described in this review is not an exhaustive or comprehensive discussion of all methods available for the detection of NO but rather a description of the most commonly used and practical methods which allow accurate and sensitive quantification of NO products/metabolites in multiple biological matrices under normal physiological conditions.
The role of the NO-ergic system in the regulation of carbohydrate metabolism and the development of diabetes mellitus
- D V Kurkin
- E E Abrosimova
- D A Bakulin
- D.V. Kurkin
Oxygen transport functions of blood and hydrogen sulfide as gas transmitter
- V V Zinchuk
- V.V. Zinchuk
Stressogenic disorders of erythrocytes and their correction with help regulatory peptides
- M G Golubeva
- M.G. Golubeva