Clinical Implication of Plasma Hydrogen Sulfide Levels in Japanese Patients with Type 2 Diabetes

Suzuki, Kunihiro; Sagara, Masaaki; Aoki, Chie; Tanaka, Seiichi; Aso, Yoshimasa

doi:10.2169/internalmedicine.56.7403

Cited by 61 publications

(56 citation statements)

References 29 publications

(29 reference statements)

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“…In our study, we found that the plasma H 2 S level in CKD patients was markedly lower than that in healthy controls, especially in the advanced CKD group, and this finding was confirmed by recent researches [5, 9, 17, 19]. We have also shown that the concentration of SHb, a compound consisting of methemoglobin and H 2 S (or another sulfide) [20], was significantly lower in CKD patients than that in the control.…”

Section: Discussionsupporting

confidence: 89%

“…Substantial evidences suggest that endogenous H 2 S presents a vital effect on signal transduction and cell protection, playing a role in nerve conduction, blood pressure control, insulin release, renal blood flow regulation, and so on. A number of diseases have been proposed to associate with decreased H 2 S level, ranging from atherosclerosis, hypertension to myocardial infarction, and diabetes mellitus [2-5]. Nevertheless, the role of H 2 S in the pathogenesis of chronic kidney disease (CKD) has not been fully investigated.…”

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confidence: 99%

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Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

et al. 2018

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Background: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H₂S) level. Nevertheless, the role of H₂S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H₂S in patients with different stages of CKD, and to identify the role of H₂S in the progression of CKD and its relationship with cardiovascular diseases. Methods: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H₂S was measured with spectrophotometry. Sulfhemoglobin, the integration of H₂S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction. Results: The plasma H₂S level (μmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 μmol/L, p < 0.01). Plasma H₂S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = –0.554, p < 0.01). The mRNA levels of cystathionine β-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H₂S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H₂S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H₂S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3–5 patients was significantly higher than that in CKD stages 1–2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative correlation between plasma H₂S level and LVEF (ρ = –0.204, p < 0.05) in CKD patients. The H₂S level also correlated negatively with cTnT concentration (ρ = –0.249, p < 0.01). Conclusions: Plasma H₂S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD patients.

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

et al. 2018

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“…Circulating levels of H 2 S are markedly reduced in diabetic animal models, such as diabetic rats (Jain et al, 2010;Suzuki et al, 2011), diabetic mice (Brancaleone et al, 2008), and also in diabetic patients (Jain et al, 2013;Suzuki et al, 2017). However, the mRNA level of CSE in the aortas of diabetic rats is not altered (Denizalti et al, 2011).…”

Section: H 2 S-related Endothelial Dysfunction In Diabetic Vascular Cmentioning

confidence: 99%

Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide

et al. 2020

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Endothelial cells are important constituents of blood vessels that play critical roles in cardiovascular homeostasis by regulating blood fluidity and fibrinolysis, vascular tone, angiogenesis, monocyte/leukocyte adhesion, and platelet aggregation. The normal vascular endothelium is taken as a gatekeeper of cardiovascular health, whereas abnormality of vascular endothelium is a major contributor to a plethora of cardiovascular ailments, such as atherosclerosis, aging, hypertension, obesity, and diabetes. Endothelial dysfunction is characterized by imbalanced vasodilation and vasoconstriction, elevated reactive oxygen species (ROS), and proinflammatory factors, as well as deficiency of nitric oxide (NO) bioavailability. The occurrence of endothelial dysfunction disrupts the endothelial barrier permeability that is a part of inflammatory response in the development of cardiovascular diseases. As such, abrogation of endothelial cell activation/inflammation is of clinical relevance. Recently, hydrogen sulfide (H 2 S), an entry as a gasotransmitter, exerts diverse biological effects through acting on various targeted signaling pathways. Within the cardiovascular system, the formation of H 2 S is detected in smooth muscle cells, vascular endothelial cells, and cardiomyocytes. Disrupted H 2 S bioavailability is postulated to be a new indicator for endothelial cell inflammation and its associated endothelial dysfunction. In this review, we will summarize recent advances about the roles of H 2 S in endothelial cell homeostasis, especially under pathological conditions, and discuss its putative therapeutic applications in endothelial inflammation-associated cardiovascular disorders.

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“…Hyperglycemia reduces the mitochondrial H 2 S pool and the plasma concentration of H 2 S, and it may deplete the buffering capacity of H 2 S in the mitochondria [94,108,109].…”

Section: Mechanism Of Damage: Cell Damaging Responses To Ros Productimentioning

confidence: 99%

“…A further target is ATP synthase in the respiratory chain: H 2 S increases cellular bioenergetics via S-sulfhydration of Complex V [122]. Since hyperglycemia reduces the H 2 S level in the cells and plasma, it will also decrease the protein S-sulfhydration and results in lower Nrf2 activity and OXPHOS efficiency [108,109].…”

Section: Mechanism Of Damage: Cell Damaging Responses To Ros Productimentioning

confidence: 99%

Hyperglycemia-Induced Endothelial Dysfunction

Gerö¹

2018

Endothelial Dysfunction - Old Concepts and New Challenges

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Glucose-induced endothelial dysfunction plays a fundamental role in the development of diabetic vascular complications and glycemic control (the foundation of diabetes care) provides limited protection against the cardiovascular complications. Therefore, identification of novel drug targets and treatment approaches for diabetes complications represent a key direction of current pharmaceutical research. The "unifying theory" of hyperglycemia-induced endothelial cell injury organizes the events of cellular dysfunction in a linear cascade and identifies mitochondrial superoxide generation as the triggering event of the injury. Exposure to high glucose concentration for long periods or repeated glycemic swings may induce changes in metabolic substrate availability and lead to mitochondrial hyperpolarization. Changes in the mitochondrial membrane potential induce superoxide production by the electron transport chain and result in oxidative stress. Mitochondrial superoxide is also responsible for the induction of other sources of reactive oxygen species (ROS) within the cells, including advanced glycation end products (AGEs) and the NADPH oxidase. Mitochondria also show morphological changes and impaired assembly of the respiratory complexes occurs, which results in cellular energy failure, cell senescence and vascular dysfunction. Current intervention strategies aim to inhibit the mitochondrial ROS production and novel therapeutic approaches are expected to provide valuable tools in diabetes therapy in the upcoming years.

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Clinical Implication of Plasma Hydrogen Sulfide Levels in Japanese Patients with Type 2 Diabetes

Cited by 61 publications

References 29 publications

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide

Hyperglycemia-Induced Endothelial Dysfunction

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