Publications by authors named "Hongfang Jin"

150 Publications

Compensatory role of endogenous sulfur dioxide in nitric oxide deficiency-induced hypertension.

Redox Biol 2021 Nov 18;48:102192. Epub 2021 Nov 18.

Department of Pediatrics, Peking University First Hospital, Beijing, China. Electronic address:

Objective: This study aimed to determine the communicational pattern of gaseous signaling molecules sulfur dioxide (SO) and nitric oxide (NO) between vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), and elucidate the compensatory role and significance of endogenous SO in the development of hypertension due to NO deficiency.

Approach And Results: Blood pressure was monitored by the tail-cuff and implantable physiological signal telemetry in L-nitro-arginine methyl ester (l-NAME)-induced hypertensive mice, and structural alterations of mouse aortic vessels were detected by the elastic fiber staining method. l-NAME-treated mice showed decreased plasma NO levels, increased SO levels, vascular remodeling, and increased blood pressure, and application of l-aspartate-β-hydroxamate, which inhibits SO production, further aggravated vascular structural remodeling and increased blood pressure. Moreover, in a co-culture system of HAECs and HASMCs, NO from HAECs did not influence aspartate aminotransferase (AAT)1 protein expression but decreased AAT1 activity in HASMCs, thereby resulting in the inhibition of endogenous SO production. Furthermore, NO promoted S-nitrosylation of AAT1 protein in HASMCs and purified AAT1 protein. Liquid chromatography with tandem mass spectrometry showed that the Cys192 site of AAT1 purified protein was modified by S-nitrosylation. In contrast, dithiothreitol or C192S mutations in HASMCs blocked NO-induced AAT1 S-nitrosylation and restored AAT1 enzyme activity.

Conclusion: Endothelium-derived NO inhibits AAT activity by nitrosylating AAT1 at the Cys192 site and reduces SO production in HASMCs. Our findings suggest that SO acts as a compensatory defense system to antagonize vascular structural remodeling and hypertension when the endogenous NO pathway is disturbed.
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http://dx.doi.org/10.1016/j.redox.2021.102192DOI Listing
November 2021

Endogenous SO Controls Cell Apoptosis: The State-of-the-Art.

Front Cell Dev Biol 2021 7;9:729728. Epub 2021 Oct 7.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

SO, previously known as the product of industrial waste, has recently been proven to be a novel gasotransmitter in the cardiovascular system. It is endogenously produced from the metabolism pathway of sulfur-containing amino acids in mammalians. Endogenous SO acts as an important controller in the regulation of many biological processes including cardiovascular physiological and pathophysiological events. Recently, the studies on the regulatory effect of endogenous SO on cell apoptosis and its pathophysiological significance have attracted great attention. Endogenous SO can regulate the apoptosis of vascular smooth muscle cells, endothelial cells, cardiomyocytes, neuron, alveolar macrophages, polymorphonuclear neutrophils and retinal photoreceptor cells, which might be involved in the pathogenesis of hypertension, pulmonary hypertension, myocardial injury, brain injury, acute lung injury, and retinal disease. Therefore, in the present study, we described the current findings on how endogenous SO is generated and metabolized, and we summarized its regulatory effects on cell apoptosis, underlying mechanisms, and pathophysiological relevance.
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http://dx.doi.org/10.3389/fcell.2021.729728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529009PMC
October 2021

Sulfur Dioxide: Endogenous Generation, Biological Effects, Detection, and Therapeutic Potential.

Antioxid Redox Signal 2021 Sep 20. Epub 2021 Sep 20.

Peking University First Hospital, 26447, Beijing, China;

Significance: Previously, sulfur dioxide (SO) was recognized as an air pollutant. However, it is found to be endogenously produced in mammalian tissues. As a new gasotransmitter, SO is involved in regulating the structure and function of blood vessels, heart, lung, gastrointestinal tract, and nervous system, etc. Recent Advances: Increasing evidence showed that endogenous SO regulates cardiovascular physiological processes, such as blood pressure control, vasodilation, maintenance of the normal vascular structure, and cardiac negative inotropy. Under pathological conditions including hypertension, atherosclerosis, vascular calcification, aging endothelial dysfunction, myocardial injury, myocardial hypertrophy, diabetic myocardial fibrosis, sepsis-induced cardiac dysfunction, pulmonary hypertension, acute lung injury, colitis, epilepsy-related brain injury, depression and anxiety, and addictive drug reward memory consolidation, endogenous SO protects against the pathological changes via different molecular mechanisms and the disturbed SO/aspartate aminotransferase pathway is likely involved in the mechanisms for the abovementioned pathologic processes.

Critical Issues: A comprehensive understanding of the biological effects of endogenous SO is extremely important for the development of novel SO therapy. In this review, we summarized the biological effects, mechanism of action, SO detection methods, and its related prodrugs.

Future Directions: Further studies should be conducted to understand the effects of endogenous SO in various physiological and pathophysiological processes and clarify its underlying mechanisms. More efficient and accurate SO detection methods, as well as specific and effective SO-releasing systems should be designed for the treatment and prevention of clinical related diseases. The translation from SO basic medical research to its clinical application is also worthy of further study.
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http://dx.doi.org/10.1089/ars.2021.0213DOI Listing
September 2021

Endogenous Taurine Downregulation Is Required for Renal Injury in Salt-Sensitive Hypertensive Rats via CBS/HS Inhibition.

Oxid Med Cell Longev 2021 25;2021:5530907. Epub 2021 Aug 25.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Although taurine is known to exert an antihypertensive effect, it is unclear whether it is involved in the mechanism for hypertension-related target organ injury. To reveal the role of endogenous taurine in renal injury formation during salt-sensitive hypertension and clarify its mechanisms, both salt-sensitive Dahl rats and salt-resistant SS-13BN rats were fed a high-salt diet (8% NaCl) and given 2% taurine for 6 weeks. Rat systolic blood pressure (SBP) was measured by the tail-cuff method and artery catheterization. Kidney ultrastructure was observed under an electron microscope. Taurine content and mRNA and protein levels of taurine synthases, cysteine dioxygenase type 1 (CDO1) and cysteine sulfinic acid decarboxylase (CSAD), were decreased in Dahl rats fed a high-salt diet. However, taurine supplementation and the resulting increase in renal taurine content reduced the increased SBP and improved renal function and structural damage in high-salt diet-fed Dahl rats. In contrast, taurine did not affect SS-13BN SBP and renal function and structure. Taurine intervention increased the renal HS content and enhanced cystathionine--synthase (CBS) expression and activity in Dahl rats fed a high-salt diet. Taurine reduced the renin, angiotensin II, and aldosterone contents and the levels of oxidative stress indices in Dahl rat renal tissues but increased antioxidant capacity, antioxidant enzyme activity, and protein expression. However, taurine failed to achieve this effect in the renal tissue of SS-13BN rats fed a high-salt diet. Pretreatment with the CBS inhibitor HA or renal CBS knockdown inhibited HS generation and subsequently blocked the effect of taurine on renin, superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2) levels in high-salt-stimulated Dahl renal slices. In conclusion, the downregulation of endogenous taurine production resulted in a decrease in the renal CBS/HS pathway. This decrease subsequently promoted renin-angiotensin-aldosterone system (RAAS) activation and oxidative stress in the kidney, ultimately contributing to renal injury in salt-sensitive Dahl rats.
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http://dx.doi.org/10.1155/2021/5530907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413057PMC
August 2021

Effectiveness and safety of dual antiplatelet therapy in coronary aneurysms caused by Kawasaki disease in children: study protocol for a multicenter randomized clinical trial.

Transl Pediatr 2021 Jul;10(7):1914-1923

Clinical Research Institute of Peking University, Beijing, China.

Background: Medium or large coronary artery aneurysm (CAA) is a serious complication of Kawasaki disease (KD) and may cause thrombosis, coronary artery stenosis, and even myocardial infarction at different stages of the disease. Dual antiplatelet therapy (aspirin plus clopidogrel) is considered for prophylaxis of coronary thrombosis in KD presenting with more than medium CAAs based on adult coronary artery disease experience and expert consensus. This paper describes the study protocol for a randomized controlled trial that measures the clinical effectiveness and safety of dual antiplatelet therapy in the thromboprophylactic treatment of KD.

Methods: The present study is a multicenter, open-label, randomized controlled trial (RCT) with a 12-month follow-up. KD patients with medium or large CAAs (Z-value ≥5), evaluated by echocardiogram and clinicians before treatment, are randomized in a 1:1 ratio and assigned to aspirin therapy alone (Control group), or dual antiplatelet (aspirin plus clopidogrel) therapy (Experimental group). Antiplatelet therapy is given to the KD patients from the time of diagnosis until the coronary artery returns to normal. Weekly or monthly follow-up visits are conducted to record compliance, recovery, and biochemical indicators and continue for one year. The primary outcome is the incidence of thrombus throughout the disease and the effective of dual antiplatelet. The secondary outcomes are the safety of dual antiplatelet drugs, platelet-related indicators, inflammatory indicators, biochemical indexes and drug-related indicators during the study period. Patients who do not meet the inclusion criteria of the RCT trial or those unwilling to provide informed consent enter the registration trial.

Discussion: This is the first study to evaluate the effectiveness and safety of dual antiplatelet therapy in coronary aneurysms caused by Kawasaki disease in children. It is hoped that this study will play an important and significant role in improving the prognosis and long-term quality of life for children with KD complicated by CAAs.

Trial Registration: Chinese Clinical Trial Registry, ChiCTR1800019181. Registered on Oct 30, 2018.
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http://dx.doi.org/10.21037/tp-21-74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349963PMC
July 2021

Editorial: Acquired Heart Disease in Children: Pathogenesis, Diagnosis and Management.

Front Pediatr 2021 15;9:725670. Epub 2021 Jul 15.

Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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http://dx.doi.org/10.3389/fped.2021.725670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319598PMC
July 2021

Efficacy of Increased Salt and Water Intake on Pediatric Vasovagal Syncope: A Meta-Analysis Based on Global Published Data.

Front Pediatr 2021 13;9:663016. Epub 2021 May 13.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

This study was designed to assess the efficacy of increased salt and water intake in the treatment of pediatric vasovagal syncope (VVS) based on a meta-analysis of global data. Following the established inclusion criteria, seven databases, Cochrane Library, EMBASE, PubMed, Web of Science, VIP, Wanfang, and China National Knowledge Infrastructure (CNKI), were searched using specific terms. The Cochrane Bias risk assessment tool was used as a quality assessment tool of the included studies, and publication bias was assessed by funnel plots. Review Manager 5.4 software was used to analyze the efficacy of the included studies, taking the negative changing rate of the head-up tilt test (HUTT) and recurrence rate of syncope or presyncope as therapeutic efficacy evaluations. In total, 5 randomized controlled trials (RCTs) were finally obtained, using the negative changing rate of the HUTT as an efficacy evaluation, while in 4 of the studies, the recurrence rate of syncope or presyncope was also evaluated. A total of 233 children with VVS were included in the salt and water intervention group. The cases in the control group were treated with non-medicinal conventional therapy. The results revealed that the negative changing rate of the HUTT in the intervention group (144/233, 61.8%) was higher than that in the control group (48/179, 26.8%), and the difference was significant ( < 0.00001). The recurrence rate of syncope or presyncope in the intervention group (85/195, 43.6%) was lower than that in the control group (86/144, 59.7%), and the difference was significant ( = 0.002). The current findings suggest that increased salt and water intake may increase the negative changing rates of the HUTT and reduce syncope or presyncope recurrence rates in pediatric patients with VVS.
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http://dx.doi.org/10.3389/fped.2021.663016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155624PMC
May 2021

Endothelial Cell-Derived SO Controls Endothelial Cell Inflammation, Smooth Muscle Cell Proliferation, and Collagen Synthesis to Inhibit Hypoxic Pulmonary Vascular Remodelling.

Oxid Med Cell Longev 2021 17;2021:5577634. Epub 2021 Apr 17.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Hypoxic pulmonary vascular remodelling (PVR) is the major pathological basis of aging-related chronic obstructive pulmonary disease and obstructive sleep apnea syndrome. The pulmonary artery endothelial cell (PAEC) inflammation, and pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy and collagen remodelling are the important pathophysiological components of PVR. Endogenous sulfur dioxide (SO) was found to be a novel gasotransmitter in the cardiovascular system with its unique biological properties. The study was aimed to investigate the role of endothelial cell- (EC-) derived SO in the progression of PAEC inflammation, PASMC proliferation, hypertrophy and collagen remodelling in PVR and the possible mechanisms. EC-specific aspartic aminotransferase 1 transgenic (EC-AAT1-Tg) mice were constructed . Pulmonary hypertension was induced by hypoxia. Right heart catheterization and echocardiography were used to detect mouse hemodynamic changes. Pathologic analysis was performed in the pulmonary arteries. High-performance liquid chromatography was employed to detect the SO content. Human PAECs (HPAECs) with lentiviruses containing AAT1 cDNA or shRNA and cocultured human PASMCs (HPASMCs) were applied . SO probe and enzyme-linked immunosorbent assay were used to detect the SO content and determine p50 activity, respectively. Hypoxia caused a significant reduction in SO content in the mouse lung and HPAECs and increases in right ventricular systolic pressure, pulmonary artery wall thickness, muscularization, and the expression of PAEC ICAM-1 and MCP-1 and of PASMC Ki-67, collagen I, and -SMA ( < 0.05). However, EC-AAT1-Tg with sufficient SO content prevented the above increases induced by hypoxia ( < 0.05). Mechanistically, EC-derived SO deficiency promoted HPAEC ICAM-1 and MCP-1 and the cocultured HPASMC Ki-67 and collagen I expression, which was abolished by andrographolide, an inhibitor of p50 ( < 0.05). Meanwhile, EC-derived SO deficiency increased the expression of cocultured HPASMC -SMA ( < 0.05). Taken together, these findings revealed that EC-derived SO inhibited p50 activation to control PAEC inflammation in an autocrine manner and PASMC proliferation, hypertrophy, and collagen synthesis in a paracrine manner, thereby inhibiting hypoxic PVR.
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http://dx.doi.org/10.1155/2021/5577634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068783PMC
May 2021

Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation.

J Adv Res 2021 03 8;29:55-65. Epub 2020 Sep 8.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Introduction: Mast cell (MC) degranulation is an important step in the pathogenesis of inflammatory reactions and allergies; however, the mechanism of stabilizing MC membranes to reduce their degranulation is unclear.

Methods: SO content in MC culture supernatant was measured by HPLC-FD. The protein and mRNA expressions of the key enzymes aspartate aminotransferase 1 (AAT1) and AAT2 and intracellular AAT activity were detected. The cAMP level in MCs was detected by immunofluorescence and ELISA. The release rate of MC degranulation marker β-hexosaminidase was measured. The expression of AAT1 and cAMP, the MC accumulation and degranulation in lung tissues were detected.

Objectives: To exam whether an endogenous sulfur dioxide (SO) pathway exists in MCs and if it serves as a novel endogenous MC stabilizer.

Results: We firstly show the existence of the endogenous SO/AAT pathway in MCs. Moreover, when AAT1 was knocked down in MCs, MC degranulation was significantly increased, and could be rescued by a SO donor. Mechanistically, AAT1 knockdown decreased the cyclic adenosine monophosphate (cAMP) content in MCs, while SO prevented this reduction in a dose-independent manner. Pretreatment with the cAMP-synthesizing agonist forskolin or the cAMP degradation inhibitor IBMX significantly blocked the increase in AAT1 knockdown-induced MC degranulation. Furthermore, in hypoxia-stimulated MCs, AAT1 protein expression and SO production were markedly down regulated, and MC degranulation was activated, which were blunted by AAT1 overexpression. The cAMP synthesis inhibitor SQ22536 disrupted the suppressive effect of AAT1 overexpression on hypoxia-induced MC degranulation. In a hypoxic environment, mRNA and protein expression of AAT1 was significantly reduced in lung tissues of rats. Supplementation of SO elevated the cAMP level and reduced perivascular MC accumulation and degranulation in lung tissues of rats exposed to a hypoxic environment .

Conclusion: SO serves as an endogenous MC stabilizer via upregulating the cAMP pathway under hypoxic circumstance.
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http://dx.doi.org/10.1016/j.jare.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020161PMC
March 2021

Metabolic Reprogramming of Vascular Endothelial Cells: Basic Research and Clinical Applications.

Front Cell Dev Biol 2021 18;9:626047. Epub 2021 Feb 18.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Vascular endothelial cells (VECs) build a barrier separating the blood from the vascular wall. The vascular endothelium is the largest endocrine organ, and is well-known for its crucial role in the regulation of vascular function. The initial response to endothelial cell injury can lead to the activation of VECs. However, excessive activation leads to metabolic pathway disruption, VEC dysfunction, and angiogenesis. The pathways related to VEC metabolic reprogramming recently have been considered as key modulators of VEC function in processes such as angiogenesis, inflammation, and barrier maintenance. In this review, we focus on the changes of VEC metabolism under physiological and pathophysiological conditions.
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http://dx.doi.org/10.3389/fcell.2021.626047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930387PMC
February 2021

Endogenous SO-dependent Smad3 redox modification controls vascular remodeling.

Redox Biol 2021 05 18;41:101898. Epub 2021 Feb 18.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China; Key Laboratory of Cardiovascular Sciences, Ministry of Education, China. Electronic address:

Sulfur dioxide (SO) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO influences its upper-stream targets have been elusive. Here we show that SO may mediate conversion of hydrogen peroxide (HO) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of HO to convert the thiol group of protein cysteine residues to a sulfenic acid group, aka cysteine sulfenylation. By using site-centric chemoproteomics, we quantified >1000 sulfenylation events in vascular smooth muscle cells in response to exogenous SO. Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO, among which is cysteine-64 of Smad3 (Mothers against decapentaplegic homolog 3), a key transcriptional modulator of transforming growth factor β signaling. Sulfenylation of Smad3 at cysteine-64 inhibits its DNA binding activity, while mutation of this site attenuates the protective effects of SO on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO in vascular pathophysiology through a redox-dependent mechanism.
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http://dx.doi.org/10.1016/j.redox.2021.101898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933484PMC
May 2021

Persulfidation of transcription factor FOXO1 at cysteine 457: A novel mechanism by which HS inhibits vascular smooth muscle cell proliferation.

J Adv Res 2021 Jan 1;27:155-164. Epub 2020 Jul 1.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Introduction: The proliferation of vascular smooth muscle cells (VSMCs) is an important physiological and pathological basis for many cardiovascular diseases. Endogenous hydrogen sulfide (HS), the third gasotransmitter, is found to preserve vascular structure by inhibiting VSMC proliferation. However, the mechanism by which HS suppresses VSMC proliferation has not been fully clear.

Objectives: This study aimed to explore whether HS persulfidates the transcription factor FOXO1 to inhibit VSMC proliferation.

Methods: After the proliferation of VSMC A7r5 cells was induced by endothelin-1 (ET-1), FOXO1 phosphorylation and proliferating cell nuclear antigen (PCNA) expression were detected by Western blotting, the degree of FOXO1 nuclear exclusion and PCNA fluorescent signals in the nucleus were detected by immunofluorescence, and the persulfidation of FOXO1 was measured through a biotin switch assay.

Results: The results showed that ET-1 stimulation increased cell proliferation, FOXO1 phosphorylation and FOXO1 nuclear exclusion to the cytoplasm in the cells. However, pretreatment with NaHS, an HS donor, successfully abolished the ET-1-induced increases in the VSMC proliferation, FOXO1 phosphorylation, and FOXO1 nuclear exclusion to the cytoplasm. Mechanistically, HS persulfidated the FOXO1 protein in A7r5 and 293T cells, and the thiol reductant DTT reversed this effect. Furthermore, the C457S mutation of FOXO1 abolished the HS-induced persulfidation of FOXO1 in the cells and the subsequent inhibitory effects on FOXO1 phosphorylation at Ser256, FOXO1 nuclear exclusion to the cytoplasm and cell proliferation.

Conclusion: Thus, our findings demonstrated that HS might inhibit VSMC proliferation by persulfidating FOXO1 at Cys457 and subsequently preventing FOXO1 phosphorylation at Ser256.
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http://dx.doi.org/10.1016/j.jare.2020.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728583PMC
January 2021

Hydrogen sulfide and vascular regulation - An update.

J Adv Res 2021 Jan 16;27:85-97. Epub 2020 May 16.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Background: Hydrogen sulfide (HS) is considered to be the third gasotransmitter after carbon monoxide (CO) and nitric oxide (NO). It plays an important role in the regulation of vascular homeostasis. Vascular remodeling have has proved to be related to the impaired HS generation.

Aim Of Review: This study aimed to summarize and discuss current data about the function of HS in vascular physiology and pathophysiology as well as the underlying mechanisms.

Key Scientific Concepts Of Review: Endogenous hydrogen sulfide (HS) as a third gasotransmitter is primarily generated by the enzymatic pathways and regulated by several metabolic pathways. HS as a physiologic vascular regulator, inhibits proliferation, regulates its apoptosis and autophagy of vascular cells and controls the vascular tone. Accumulating evidence shows that the downregulation of HS pathway is involved in the pathogenesis of a variety of vascular diseases, such as hypertension, atherosclerosis and pulmonary hypertension. Alternatively, HS supplementation may greatly help to prevent the progression of the vascular diseases by regulating vascular tone, inhibiting vascular inflammation, protecting against oxidative stress and proliferation, and modulating vascular cell apoptosis, which has been verified in animal and cell experiments and even in the clinical investigation. Besides, HS system and angiotensin-converting enzyme (ACE) inhibitors play a vital role in alleviating ischemic heart disease and left ventricular dysfunction. Notably, sulfhydryl-containing ACEI inhibitor zofenopril is superior to other ACE inhibitors due to its capability of HS releasing, in addition to ACE inhibition. The design and application of novel HS donors have significant clinical implications in the treatment of vascular-related diseases. However, further research regarding the role of HS in vascular physiology and pathophysiology is required.
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http://dx.doi.org/10.1016/j.jare.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728588PMC
January 2021

Hydrogen sulfide regulates insulin secretion and insulin resistance in diabetes mellitus, a new promising target for diabetes mellitus treatment? A review.

J Adv Res 2021 Jan 26;27:19-30. Epub 2020 Feb 26.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

Background: Insulin resistance and impaired insulin secretion lead to disorders of glucose metabolism, which contributes to the development of diabetes. Hydrogen sulfide (H2S), a novel gasotransmitter, is found to play important roles in regulation of glucose metabolism homeostasis.

Aim Of Review: This study aimed to summarize and discuss current data about the function of H2S in insulin secretion and insulin resistance regulation as well as the underlying mechanisms.

Key Scientific Concepts Of Review: HS could be endogenously produced in islet β cells, liver, adipose, skeletal muscles, and the hypothalamus, and regulates local and systemic glucose metabolism. It is reported that HS suppresses insulin secretion, promotes or reduces the apoptosis of islet β cells. It plays important roles in the regulation of insulin sensitivity in insulin responsive tissues. HS inhibits glucose uptake and glycogen storage, and promotes or inhibits gluconeogenesis, mitochondrial biogenesis and mitochondrial bioenergetics in the liver. In adipose tissue, several investigators indicated that H2S promoted glucose uptake in adipocytes, while other studies reported that HS inhibits this process. HS has also been shown to promote adipogenesis, inhibit lipolysis, and regulate adiponectin and MCP-1 secretion from adipocytes. In skeletal muscle, HS increases glucose uptake and improves insulin sensitivity. It is also observed that HS modulates circadian-clock genes in muscle. Hypothalamic CBS/HS pathway reduces obesity and improves insulin sensitivity via the brain-adipose interaction. Most studies indicated plasma HS levels decreased in diabetic patients. However, the mechanisms by which HS regulates systemic glucose metabolism remain unclear. Whether HS acts as a new promising target for diabetes mellitus treatment merits further studies.
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http://dx.doi.org/10.1016/j.jare.2020.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728586PMC
January 2021

Post-translational Modifications of IκBα: The State of the Art.

Front Cell Dev Biol 2020 5;8:574706. Epub 2020 Nov 5.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

The nuclear factor-kappa B (NF-κB) signaling pathway regulates a variety of biological functions in the body, and its abnormal activation contributes to the pathogenesis of many diseases, such as cardiovascular and respiratory diseases and cancers. Therefore, to ensure physiological homeostasis of body systems, this pathway is strictly regulated by IκBα transcription, IκBα synthesis, and the IκBα-dependent nuclear transport of NF-κB. Particularly, the post-translational modifications of IκBα including phosphorylation, ubiquitination, SUMOylation, glutathionylation and hydroxylation are crucial in the abovementioned regulatory process. Because of the importance of the NF-κB pathway in maintaining body homeostasis, understanding the post-translational modifications of IκBα can not only provide deeper insights into the regulation of NF-κB pathway but also contribute to the development of new drug targets and biomarkers for the diseases.
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http://dx.doi.org/10.3389/fcell.2020.574706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674170PMC
November 2020

Comorbidity of Neurally Mediated Syncope and Allergic Disease in Children.

Front Immunol 2020 28;11:1865. Epub 2020 Aug 28.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Neurally mediated syncope (NMS) is the most common underlying disease of pediatric syncope, which generally includes vasovagal syncope (VVS), postural tachycardia syndrome (POTS), and situational syncope. Allergic diseases involving the respiratory system, digestive system, skin, and other systems are prevalent in children. In recent years, increasing attention has been paid to children with the comorbidity of NMS and allergic diseases. This article reviews the featured clinical manifestations and pathogenesis of the comorbidity according to the progress of related studies. Clinical studies have shown that the comorbidity rate of pediatric VVS and/or POTS with allergic diseases amounts to ~30-40%, referring to the whole population of children with VVS and/or POTS. Additionally, children with the comorbidity present some relatively special clinical characteristics. A series of mechanisms or regulatory factors relating to allergies, such as the imbalance of vasoactive elements, dysfunction of the autonomic nervous system (ANS), and autoimmunity may play a role in the development of the comorbidity. Moreover, 90% of children with cough syncope, a type of situational syncope, have a history of asthma, indicating a potential relationship between asthma and NMS. Further studies exploring the clinical characteristics and pathogenesis of the comorbidity are still needed to aid in the diagnosis and treatment of children with NMS.
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http://dx.doi.org/10.3389/fimmu.2020.01865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485378PMC
April 2021

Postural Tachycardia Syndrome in Children and Adolescents: Pathophysiology and Clinical Management.

Front Pediatr 2020 20;8:474. Epub 2020 Aug 20.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Postural tachycardia syndrome (POTS), characterized by chronic (≥6 months) orthostatic intolerance symptoms with a sustained and excessive heart rate increase while standing without postural hypotension, is common in children and adolescents. Despite the unclear pathogenesis of POTS, the present opinion is that POTS is a heterogeneous and multifactorial disorder that includes altered central blood volume, abnormal autonomic reflexes, "hyperadrenergic" status, damaged skeletal muscle pump activity, abnormal local vascular tension and vasoactive factor release, mast cell activation, iron insufficiency, and autoimmune dysfunction. A number of pediatric POTS patients are affected by more than one of these pathophysiological mechanisms. Therefore, individualized treatment strategies are initiated in the management of POTS, including basal non-pharmacological approaches (e.g., health education, the avoidance of triggers, exercise, or supplementation with water and salt) and special pharmacological therapies (e.g., oral rehydration salts, midodrine hydrochloride, and metoprolol). As such, the recent progress in the pathogenesis, management strategies, and therapeutic response predictors of pediatric POTS are reviewed here.
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http://dx.doi.org/10.3389/fped.2020.00474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468430PMC
August 2020

Orthostatic Hypertension in Children: An Update.

Front Pediatr 2020 29;8:425. Epub 2020 Jul 29.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

The concept of orthostatic hypertension in children was first proposed in 2012. The pathogenesis is not clear by now. Orthostatic hypertension is one of the important causes of orthostatic intolerance in children and is related to the development of essential hypertension in the future. It is commonly seen in older children, with dizziness and syncope as their main clinical manifestations. Non-drug therapy is the commonly used treatment strategy, which is effective to improve the orthostatic intolerance symptoms. In this paper, we reviewed the clinical studies on the pathogenesis, clinical characteristics, diagnostic criteria, and treatment of orthostatic hypertension in children, aiming to provide new insights for the future studies on pediatric orthostatic hypertension.
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http://dx.doi.org/10.3389/fped.2020.00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403181PMC
July 2020

Sitting-induced hemodynamic changes and association with sitting intolerance in children and adolescents: a cross-sectional study.

Sci Rep 2020 08 18;10(1):13921. Epub 2020 Aug 18.

Department of Pediatrics, Peking University First Hospital, No. 1, Xi'an-men Street, West District, Beijing, 100034, China.

Hemodynamic alteration with postural change from supine to sitting has been unclear in the young. In the cross-sectional study, 686 participants (371 boys and 315 girls, aged 6-18 years) were recruited from 4 schools in Kaifeng city, the central area of China. The active sitting test was performed to obtain heart rate (HR) and blood pressure (BP) changes from supine to sitting in children and adolescents. Hemodynamic change-associated sitting intolerance was analyzed. In the study participants, the 95th percentile (P) values of changes in HR and BP within 3 min from supine to sitting were 25 beats/min and 18/19 mm Hg, respectively. Sixty-six participants had sitting intolerance symptoms. Compared with participants without sitting intolerance symptoms, those with symptoms more frequently had HR increase ≥ P or BP increase ≥ P within 3 min from supine to sitting (P < 0.001). Risk factors for sitting intolerance were age (odds ratio 1.218, 95% confidence interval 1.072-1.384, P = 0.002) and changes in HR or BP ≥ P within 3 min after sitting (odds ratio 2.902, 95% confidence interval 1.572-5.357, P = 0.001). We firstly showed hemodynamic changing profiles from supine to sitting and their association with sitting intolerance in children and adolescents. Sitting tachycardia is likely suggested with a change in HR ≥ 25 beats/min and sitting hypertension with a change in BP ≥ 20/20 mm Hg when changing from supine to sitting within 3 min. The age and changes in HR or BP were independent risk factors for sitting intolerance.
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http://dx.doi.org/10.1038/s41598-020-70925-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435175PMC
August 2020

Sulfur Dioxide: An Endogenous Protector Against Myocardial Injury.

J Cardiovasc Pharmacol 2020 10;76(4):389-396

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Sulfur dioxide (SO2) was previously known as a harmful gas in air pollution. Recently, it was reported that SO2 can be endogenously generated in cardiovascular tissues. Many studies have revealed that endogenous SO2 has important physiological and pathophysiological significance and pharmacological potential. As a novel gasotransmitter, SO2 has important regulatory effects on the heart. It has a dose-dependent negative inotropic effect on cardiac function, in which L-type calcium channels are involved. SO2 can also attenuate myocardial injury caused by various harmful stimuli and play an important role in myocardial ischemia-reperfusion injury and myocardial hypertrophy. These effects are thought to be linked to its ability to reduce inflammation and as an antioxidant. In addition, SO2 regulates cardiomyocyte apoptosis and autophagy. Therefore, endogenous SO2 plays an important role in maintaining cardiovascular system homeostasis. In the present review, the literature concerning the metabolism of endogenous SO2, its cardiac toxicological effects and physiological regulatory effects, mechanisms for SO2-mediated myocardial protection and its pharmacological applications are summarized and discussed.
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http://dx.doi.org/10.1097/FJC.0000000000000882DOI Listing
October 2020

Risk Factors for Orthostatic Hypertension in Children.

J Pediatr 2020 12 12;227:212-217.e1. Epub 2020 Jul 12.

Department of Pediatrics, Peking University First Hospital, Beijing, China; Key Laboratory of Cardiovascular Sciences, Ministry of Education, Beijing, China. Electronic address:

Objective: To investigate the risk factors for orthostatic hypertension in children.

Study Design: Eighty children with orthostatic hypertension were enrolled in the group with orthostatic hypertension, and 51 healthy children served as the control group. Demographic characteristics, clinical history, daily water intake, nightly sleep duration, the results of the standing test, and complete blood count were recorded and compared between the 2 groups. The risk factors for pediatric orthostatic hypertension were determined by logistic regression analysis.

Results: Body mass index and red blood cell distribution width were higher in the group with orthostatic hypertension than in healthy children, whereas daily water intake and sleep duration were lower. Logistic regression analyses showed that, if a child suffered from overweight, suffered from obesity, had a daily water intake of less than 800 mL, or had a red blood cell distribution width that was increased by 1%, the risk of orthostatic hypertension would be increased by 6.069 times (95% CI, 1.375-26.783; P < .05), 7.482 times (95% CI, 1.835-30.515; P < .01), 4.027 times (95% CI, 1.443-11.241; P < .01), or 4.008 times (95% CI, 1.698-9.461; P < .01), respectively. However, if the sleep duration was increased by 1 hour, the risk of developing orthostatic hypertension would be decreased by 74.3% (95% CI, 54.6%-85.4%, P < .01).

Conclusions: Increased body mass index, inadequate water intake and sleep duration, and elevated red blood cell distribution width were identified as risk factors for pediatric orthostatic hypertension.
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http://dx.doi.org/10.1016/j.jpeds.2020.07.030DOI Listing
December 2020

Endothelin-1 Downregulates Sulfur Dioxide/Aspartate Aminotransferase Pathway via Reactive Oxygen Species to Promote the Proliferation and Migration of Vascular Smooth Muscle Cells.

Oxid Med Cell Longev 2020 28;2020:9367673. Epub 2020 Jan 28.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

The regulatory mechanisms for proliferation and migration of vascular smooth muscle cells have not yet been clear. The present study was designed to investigate whether and how endothelin-1 (ET-1) impacted the generation of endogenous sulfur dioxide (SO) in rat vascular smooth muscle cell (VSMC) proliferation and migration. Primary VSMCs and purified aspartate aminotransferase (AAT) protein were used in this study. We found that in the presence of ET-1, the expression of PCNA and Ki-67 was upregulated and the migration of VSMCs was promoted, while the AAT activity and SO levels in VSMCs were reduced without any changes in AAT1 and AAT2 expression. SO supplementation successfully prevented the ET-1-facilitated expression of PCNA and Ki-67 and the migration of VSMCs. Interestingly, ET-1 significantly increased reactive oxygen species (ROS) production in association with SO/AAT pathway downregulation in VSMCs compared with controls, while the ROS scavenger N-acetyl-L-cysteine (NAC) and the antioxidant glutathione (GSH) significantly abolished the ET-1-stimulated downregulation of the SO/AAT pathway. Moreover, the AAT activity was reduced in purified protein after the treatment for 2 h. However, NAC and GSH blocked the hydrogen peroxide-induced AAT activity reduction. In conclusion, our results suggest that ET-1 results in the downregulation of the endogenous SO/AAT pathway via ROS generation to enhance the proliferation and migration of VSMCs.
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http://dx.doi.org/10.1155/2020/9367673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008293PMC
September 2020

Negative auto-regulation of sulfur dioxide generation in vascular endothelial cells: AAT1 S-sulfenylation.

Biochem Biophys Res Commun 2020 Feb 19. Epub 2020 Feb 19.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China. Electronic address:

Recently, endogenous sulfur dioxide (SO) has been found to exert an important function in the cardiovascular system. However, the regulatory mechanism for SO generation has not been entirely clarified. Hence, we aimed to explore the possible auto-regulation of endogenous SO generation and its mechanisms in vascular endothelial cells. We showed that SO did not affect the protein expression of aspartate aminotransferase 1 (AAT1), a major SO synthesis enzyme, but significantly inhibited AAT activity in primary human umbilical vein endothelial cells (HUVECs) and porcine purified AAT1 protein. An AAT1 enzymatic kinetic study showed that SO reduced the Vmax (1.89 ± 0.10 vs 2.55 ± 0.12, μmol/mg/min, P < 0.05) and increased the Km (35.97 ± 9.54 vs 19.33 ± 1.76 μmol/L, P < 0.05) values. Furthermore, SO induced S-sulfenylation of AAT1 in primary HUVECs and purified AAT1 protein. LC-MS/MS analysis indicated that SO sulfenylated AAT1 at Cys192. Mechanistically, thiol reductant DTT treatment or C192S mutation prevented SO-induced AAT1 sulfenylation and the subsequent inhibition of AAT activity in purified AAT1 protein and primary HUVECs. Our findings reveal, for the first time, a mechanism of auto-regulation of SO generation through sulfenylation of AAT1 at Cys192 to suppress AAT activity in vascular endothelial cells. These findings will greatly deepen the understanding of regulatory mechanisms in the cardiovascular homeostasis.
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http://dx.doi.org/10.1016/j.bbrc.2020.02.040DOI Listing
February 2020

Macrophage-derived sulfur dioxide is a novel inflammation regulator.

Biochem Biophys Res Commun 2020 04 10;524(4):916-922. Epub 2020 Feb 10.

Department of Pediatrics, Peking University First Hospital, Beijing, China. Electronic address:

Macrophage-mediated inflammation is a key pathophysiological component of cardiovascular diseases, but the underlying mechanisms by which the macrophage regulates inflammation have been unclear. In our study, we, for the first time, showed an endogenous sulfur dioxide (SO) production in RAW267.4 macrophages by using HPLC and SO-specific fluorescent probe assays. Moreover, the endogenous SO generating enzyme aspartate aminotransferase (AAT) was found to be expressed by the macrophages. Furthermore, we showed that AAT2 knockdown triggered spontaneous macrophage-mediated inflammation, as represented by the increased TNF-α and IL-6 levels and the enhanced macrophage chemotaxis; these effects could be reversed by the treatment with a SO donor. Mechanistically, AAT2 knockdown activated the NF-κB signaling pathway in macrophages, while SO successfully rescued NF-κB activation. In contrast, forced AAT2 expression reversed AngII-induced NF-κB activation and subsequent macrophage inflammation. Moreover, treatment with a SO donor also alleviated macrophage infiltration in AngII-treated mouse hearts. Collectively, our data suggest that macrophage-derived SO is an important regulator of macrophage activation and it acts as an endogenous "on-off switch" in the control of macrophage activation. This knowledge might enable a new therapeutic strategy for cardiovascular diseases.
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http://dx.doi.org/10.1016/j.bbrc.2020.02.013DOI Listing
April 2020

Baroreflex Sensitivity Predicts Response to Metoprolol in Children With Vasovagal Syncope: A Pilot Study.

Front Neurosci 2019 13;13:1329. Epub 2019 Dec 13.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

To explore the role of baroreflex sensitivity (BRS) in the head-up tilt test (HUTT) in predicting the therapeutic response of vasovagal syncope (VVS) patients to metoprolol. Vasovagal syncope patients treated with metoprolol were enrolled in this study and were classified as responders or non-responders according to changes in their symptom scores before and after metoprolol treatment. Values of BRS in the supine position and at positive response occurrence in the HUTT were obtained, and BRS changes from supine to positive response occurrence were calculated. Differences between responders and non-responders were analyzed. Receiver operating characteristic curve analysis was performed to assess the value of BRS for predicting the therapeutic efficacy of metoprolol in pediatric patients with VVS. Forty patients (14 boys; 11.8 ± 2.5 years) diagnosed with VVS were recruited in the study, 28 of whom were verified to be responders to metoprolol and 12 of whom were verified as non-responders. They did not show any differences in baseline characteristics and hemodynamics in the HUTT ( > 0.05). However, the responders had an obviously increased supine BRS value compared to the non-responders (16.9 ± 7.7 ms/mmHg vs. 7.6 ± 3.8 ms/mmHg; < 0.01). No difference in BRS at positive response occurrence was observed between the two groups (8.9 ± 8.5 ms/mmHg vs. 10.6 ± 9.8 ms/mmHg; > 0.05). Accordingly, the changes in the BRS of responders were more obvious than in non-responders (8.0 ± 7.8 ms/mmHg vs. -3.0 ± 10.4 ms/mmHg; < 0.01). The area under the receiver operating characteristic curve for the predictive value of supine BRS was 0.887 (95% CI, 0.779-0.995; < 0.01). A cut-off value of 10 ms/mmHg yielded a sensitivity and specificity of 82 and 83%, respectively, in predicting the therapeutic efficacy of metoprolol in pediatric VVS patients. The area under the receiver operating characteristic curve for the predictive value of BRS changes was 0.827 (95% CI, 0.693-0.962; < 0.01). A cut-off value of 4 ms/mmHg yielded a sensitivity and specificity of 71 and 83%, respectively. Baroreflex sensitivity may predict the response of children with VVS to metoprolol.
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http://dx.doi.org/10.3389/fnins.2019.01329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923178PMC
December 2019

L-Cystathionine Protects against Homocysteine-Induced Mitochondria-Dependent Apoptosis of Vascular Endothelial Cells.

Oxid Med Cell Longev 2019 25;2019:1253289. Epub 2019 Nov 25.

Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.

The study was aimed at investigating the effects of L-cystathionine on vascular endothelial cell apoptosis and its mechanisms. Cultured human umbilical vein endothelial cells (HUVECs) were used in the study. Apoptosis of vascular endothelial cells was induced by homocysteine. Apoptosis, mitochondrial superoxide anion, mitochondrial membrane potential, mitochondrial permeability transition pore (MPTP) opening, and caspase-9 and caspase-3 activities were examined. Expression of Bax, Bcl-2, and cleaved caspase-3 was tested and BTSA1, a Bax agonist, and HUVEC Bax overexpression was used in the study. Results showed that homocysteine obviously induced the apoptosis of HUVECs, and this effect was significantly attenuated by the pretreatment with L-cystathionine. Furthermore, L-cystathionine decreased the production of mitochondrial superoxide anion and the expression of Bax and restrained its translocation to mitochondria, increased mitochondrial membrane potential, inhibited mitochondrial permeability transition pore (MPTP) opening, suppressed the leakage of cytochrome c from mitochondria into the cytoplasm, and downregulated activities of caspase-9 and caspase-3. However, BTSA1, a Bax agonist, or Bax overexpression successfully abolished the inhibitory effect of L-cystathionine on Hcy-induced MPTP opening, caspase-9 and caspase-3 activation, and HUVEC apoptosis. Taken together, our results indicated that L-cystathionine could protect against homocysteine-induced mitochondria-dependent apoptosis of HUVECs.
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http://dx.doi.org/10.1155/2019/1253289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899331PMC
May 2020

Heart Rate Variability Predicts Therapeutic Response to Metoprolol in Children With Postural Tachycardia Syndrome.

Front Neurosci 2019 12;13:1214. Epub 2019 Nov 12.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Purpose: To improve the metoprolol therapeutic effectiveness, we aimed to explore whether baseline heart rate variability (HRV) indicators before metoprolol treatment were useful for predicting its efficacy for postural tachycardia syndrome (POTS).

Methods: We recruited 45 children with POTS who received metoprolol and 17 healthy controls. All children underwent a standing test or basic head-up tilt test and 24-h dynamic electrocardiography before treatment. After 3 months of metoprolol, therapeutic responsiveness was evaluated. The usefulness of baseline HRV parameters in predicting the effectiveness of metoprolol was studied and the long-term cumulative symptom rate was analyzed.

Results: The baseline HRV frequency domain indicators for power, ultra-low frequency, very-low frequency, low frequency (LF), high frequency (HF), and total power (TP) as well as time domain indicators were significantly lower for responders than non-responders to metoprolol; however, low-frequency normalized units and LF/HF ratio were markedly greater for responders than non-responders. On series-parallel analysis, combined baseline triangular (TR) index ≤ 33.7 and standard deviation of all normal-to-normal intervals (SDNN) index ≤ 79.0 ms as cut-off values yielded sensitivity, specificity and accuracy of 85.3, 81.8, and 84.4%, respectively, to predict therapeutic responsiveness to metoprolol. On long-term follow-up, the cumulative symptom rate was significantly higher with TR index > 33.7 and SDNN index ≤ 79.0 ms, TR index ≤ 33.7 and SDNN index > 79.0 ms or TR index > 33.7 and SDNN index > 79.0 ms than TR index ≤ 33.7 and SDNN index ≤ 79.0 ms ( < 0.05).

Conclusion: Combined TR index ≤ 33.7 and SDNN index ≤ 79.0 ms were useful preliminary measures to predict therapeutic response to metoprolol in pediatric POTS.
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http://dx.doi.org/10.3389/fnins.2019.01214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861190PMC
November 2019

Endogenous hydrogen sulfide sulfhydrates IKKβ at cysteine 179 to control pulmonary artery endothelial cell inflammation.

Clin Sci (Lond) 2019 10;133(20):2045-2059

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Background: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear.

Methods: Purified recombinant human inhibitor of κB kinase subunit β (IKKβ) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein.

Results: We showed that hydrogen sulfide (H2S) inhibited IKKβ activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKβ activity directly via sulfhydrating IKKβ at cysteinyl residue 179 (C179) in purified recombinant IKKβ protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKβ inactivation. Furthermore, to demonstrate the significance of IKKβ sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKβ. In purified IKKβ protein, C179S mutation of IKKβ abolished H2S-induced IKKβ sulfhydration and the subsequent IKKβ inactivation. In human PAECs, C179S mutation of IKKβ blocked H2S-inhibited IKKβ activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKβ abolished the inhibitory effect of H2S on IKKβ activation and pulmonary vascular inflammation and remodeling.

Conclusion: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKβ via sulfhydrating IKKβ at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.
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http://dx.doi.org/10.1042/CS20190514DOI Listing
October 2019
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