Plasma Endothelin-1 Levels Research Articles

Cardiomyocyte-specific deletion of endothelin receptor A (ETA) obliterates cardiac aging through regulation of mitophagy and ferroptosis

Advanced aging evokes unfavorable changes in the heart including cardiac remodeling and contractile dysfunction although the underlying mechanism remains elusive. This study was conducted to evaluate the role of endothelin-1 (ET-1) in the pathogenesis of cardiac aging and mechanism involved. Echocardiographic and cardiomyocyte mechanical properties were determined in young (5–6 mo) and aged (26–28 mo) wild-type (WT) and cardiomyocyte-specific ETA receptor knockout (ETAKO) mice. GSEA enrichment identified differentially expressed genes associated with mitochondrial respiration, mitochondrial protein processing and mitochondrial depolarization in cardiac aging. Aging elevated plasma levels of ET-1, Ang II and suppressed serum Fe2+, evoked cardiac remodeling (hypertrophy and interstitial fibrosis), contractile defects (fractional shortening, ejection fraction, cardiomyocyte peak shortening, maximal velocity of shortening/relengthening and prolonged relengthening) and intracellular Ca2+ mishandling (dampened intracellular Ca2+ release and prolonged decay), the effects with the exception of plasma AngII, ET-1 and Fe2+ were mitigated by ETAKO. Advanced age facilitated O2− production, carbonyl protein damage, cardiac hypertrophy (GATA4, ANP, NFATc3), ER stress, ferroptosis, compromised autophagy (LC3B, Beclin-1, Atg7, Atg5 and p62) and mitophagy (parkin and FUNDC1), and deranged intracellular Ca2+ proteins (SERCA2a and phospholamban), the effects of which were reversed by ETA ablation. ET-1 provoked ferroptosis in vitro, the response was nullified by the ETA receptor antagonist BQ123 and mitophagy inducer CsA. ETA but not ETB receptor antagonism reconciled cardiac aging, which was abrogated by inhibition of mitophagy and ferroptosis. These findings collectively denote promises of targeting ETA, mitophagy and ferroptosis in the management of aging-associated cardiac remodeling and contractile defect.

Determining the Effect of L-arginine and Physical Activity on the Plasma Levels of Endothelin-1 and Tissue Inhibitor of Metalloproteinase-1 in Postmenopausal Women with Hypertension

Background and Objectives Exercise and L-arginine supplementation are known as effective strategies for treating hypertension. The aim of the present study was to determine the effect of aerobic exercise and L-arginine consumption on tissue inhibitor of metalloproteinase-1 (TIMP-1) and endothelin-1 (ET-1) levels in postmenopausal women with hypertension. Subjects and Methods In this quasi-experimental research, 40 postmenopausal women with hypertension were divided into four equal groups including exercise, exercise + L-arginine, L-arginine, and placebo groups. Interventions of aerobic exercise (60-75% of maximum heart rate) and L-arginine supplementation (6 g/day) were completed for 12 weeks. Forty-eight hours after the last intervention session, blood samples similar to the pre-test were collected to measure TIMP-1 and ET-1 levels using ELISA method. Results Plasma ET-1 levels in the training and training + L-arginine groups were significantly reduced compared to the placebo and L-arginine groups. In addition, plasma TIMP-1 increased significantly in the exercise group and exercise + L-arginine group compared to the placebo group. No synergistic effect was observed on TIMP-1 and ET-1 levels, despite the greater effect of exercise combined with L-arginine supplementation. Conclusion According to the results of the present research, improved blood pressure in adaptation to aerobic exercises is associated with reduced ET-1 and increased TIMP-1. L-arginine supplement, either alone or in combination with aerobic exercise, has no significant effect on TIMP-1 and ET-1 changes.

Reactive oxygen species mitigate perturbations in coronary microvascular tone in exercising swine with multiple risk factors

Abstract Background Multiple cardiovascular risk factors, such as diabetes mellitus (DM), chronic kidney disease (CKD) and dyslipidemia are known to induce inflammation and microvascular dysfunction contributing to impaired myocardial perfusion. We previously observed that a combination of DM, high fat diet (HFD) and CKD produced an increase in coronary microvascular tone in awake swine, resulting in perturbations in myocardial O2 balance. The increased microvascular tone was mediated by an impaired NO bioavailability and was accompanied by increased myocardial levels of reactive oxygen species (ROS) and increased circulating levels of endothelin (ET). Hypothesis: In the present study in swine, we tested the hypothesis that ROS scavenging and ET receptor blockade reduce coronary microvascular tone, improving myocardial O2 delivery and O2 balance in swine with DM+HFD+CKD. Methods DM (streptozotocin), HFD and CKD (renal artery embolization) were induced in 13 female swine (DM+HFD+CKD), while 11 healthy female swine on normal pig chow served as controls (Normal). After 6 months, the effects of ROS scavenging and ET receptor blockade on coronary microvascular tone were studied at rest and during graded treadmill exercise. Results 6 months of sustained hyperglycemia (18.1±1.0 in DM+HFD+CKD vs 8.5±0.6 mmol/l in Normal), hypercholesterolemia (12.3±2.0 vs 1.7±0.1 mmol/l) and renal dysfunction (plasma creatinine: 165±7 vs 119±3 µmol/l) were accompanied by systemic inflammation (TNF 52±5 vs 25±6 pg/ml), elevated ET plasma levels, (36±2 vs 29±2 pg/ml), and oxidative stress (myocardial PGF2a 12.9±0.8 vs 10.2±0.5 pg/mg protein, all P<0.05 by t-test). Surprisingly, in vivo ROS scavenging (TEMPOL+MPG) reduced myocardial O2 delivery (forcing an increased myocardial O2 extraction) in DM+HFD+CKD swine, indicative of a coronary microvascular constrictor response to ROS scavenging, implying a ROS-mediated vasodilator influence (Fig. A, B). In vitro experiments, using catalase in coronary small arteries, suggested a vasodilator role for hydrogen peroxide (H2O2) in DM+HFD+CKD but not in Normal swine. A switch from NO towards to H2O2 in the regulation of coronary microvascular tone was further supported by an increase in ceramide production (138±34 vs 45±4 nmol/ml, P<0.05) and increased activity of catalase in the myocardium (44±3 vs 31±4 nmol/min/mg, P<0.05) of DM+HFD+CKD vs Normal swine. Despite elevated ET plasma levels in DM+HFD+CKD swine, combined ETA/ETB receptor blockade with tezosentan did not affect myocardial O2 balance in either Normal or DM+HFD+CKD swine (Fig C, D). Conclusion In swine, 6 months exposure to multiple risk factors resulted in increased oxidative stress that paradoxically acted to mitigate perturbations in coronary microvascular tone via an H2O2-mediated coronary vasodilator influence. Despite an increase in circulating ET levels, we found no evidence for an increased ET-1 mediated coronary vasoconstrictor influence.

Abstract 17167: Uncontrolled Hypertension Increases Endothelin-1-Induced Contractile Response of Coronary Microvasculature Both Before and After Cardioplegia and Cardiopulmonary Bypass

Introduction: Hypertensive patients undergoing cardiopulmonary bypass (CPB) have worse clinical outcomes, and coronary microvascular dysfunction may play a role. Endothelin-1 (ET-1), a vasoactive biopeptide, is increased in cardiomyocytes during the hypertrophic response to hypertension and in patients following CPB. Differential effects of hypertension on coronary microvascular reactivity and molecular signaling pathways following CPB have yet to be elucidated. Aims: This study investigated the effects of well-controlled and uncontrolled hypertension on CPB-induced changes in coronary microvascular vasoconstriction to ET-1 and associated signaling using unique in vitro microvascular reactivity studies, RNA deep sequencing, and established molecular methods. Methods: Coronary microvessels (<200um) were harvested from atrial samples from patients with no hypertension (NH), well-controlled hypertension (CH), and uncontrolled hypertension (UH) before and after CPB. In vitro contractile response to ET-1 was assessed using video microscopy. Protein expression and receptor localization were measured using immunoblotting and immunohistochemistry, respectively. Enzyme-linked immunosorbent assay was used to quantify plasma concentration of ET-1. Results: Pre-CPB contractile response of coronary microvessels to ET-1 in UH was increased compared to NH or CH (p <0.05). Post-CPB contractile response was impaired overall (p <0.05). Between groups, contractile response in CH and NH was comparable while response in UH was higher (p <0.05). Plasma ET-1 increased post-CPB (p = 0.18). Total protein levels and localization of ET A R and ET B R were unchanged post-CPB. Conclusions: While CPB overall blunted vasomotor contractile response of coronary microvessels to ET-1, UH was associated with relatively increased vasoconstriction compared to CH and NH. Changes in plasma ET-1, ET A R and ET B R levels or localization did not contribute to these effects.

Endothelin Modulates Rhythm Disturbances and Autonomic Responses to Acute Emotional Stress in Rats.

The ubiquitous peptide endothelin is currently under investigation as a modulatory factor of autonomic responses to acute emotional stress. Baseline plasma levels of endothelin alter blood pressure responses, but it remains unclear whether autonomic activity and arrhythmogenesis (i.e., brady- or tachyarrhythmias) are affected. We recorded sympathetic and vagal indices (derived from heart rate variability analysis), rhythm disturbances, voluntary motion, and systolic blood pressure after acute emotional stress in conscious rats with implanted telemetry devices. Two strains were compared, namely wild-type and ETB-deficient rats, the latter displaying elevated plasma endothelin. No differences in heart rate or blood pressure were evident, but sympathetic responses were blunted in ETB-deficient rats, contrasting prompt activation in wild-type rats. Vagal withdrawal was observed in both strains at the onset of stress, but vagal activity was subsequently restored in ETB-deficient rats, accompanied by low voluntary motion during recovery. Reflecting such distinct autonomic patterns, frequent premature ventricular contractions were recorded in wild-type rats, as opposed to sinus pauses in ETB-deficient rats. Thus, chronically elevated plasma endothelin levels blunt autonomic responses to acute emotional stress, resulting in vagal dominance and bradyarrhythmias. Our study provides further insights into the pathophysiology of stress-induced tachyarrhythmias and syncope.

The Association of Endothelin-1 with Early and Long-Term Mortality in COVID-19.

(1) Background: Endothelial dysfunction is a key mechanism in the pathogenesis of COVID-19. High endothelin-1 during COVID-19 is associated with severe complications and increased mortality rates during hospitalization. This study is aimed to investigate the association of endothelin-1 levels with the risk of 30-day and 12-month all-cause mortality in patients with prior COVID-19. (2) Methods: A prospective study was conducted involving patients with COVID-19 in Karaganda, Kazakhstan. The level of endothelin-1 in the blood serum was evaluated by ELISA. Univariate and multivariate Cox regression was used to determine factors and significance of endothelin-1 associated with the risk of mortality within 30 and 365 days from hospitalization. (3) Results: The median endothelin-1 was higher in the group of patients who passed away within 30 days. The group showed statistically significant differences when compared to healthy volunteers from the control group (p = 0.0001), surviving patients (p = 0.001), and those who passed away within a year (p = 0.002). (4) Conclusions: Endothelin-1 levels are associated with increased mortality risk during the acute period of COVID-19, while plasma endothelin-1 level association with COVID-19 survivor mortality risk does not persist after 12 months.

Could tear endothelin-1 levels be associated with disability in multiple sclerosis?

Background: Endothelin-1 (ET-1) is a potent vasoconstrictor substance mainly secreted by endothelial cells. Increased ET-1 levels in plasma or cerebrospinal fluid (CSF) have been identified in multiple sclerosis (MS). We aimed to analyze tear ET-1 levels; visual evoked potential (VEP) and disability scores in patients with MS and in healthy controls. Methods: Adult patients (18-65 year-old) diagnosed with MS according to the McDonald criteria, and healthy controls were recruited for the study. Demographic features, VEP, and tear ET-1 levels were evaluated. Disability in the MS group was assessed and grouped by EDSS score (<3 vs. ≥3). The EDSS score in healthy controls was zero. Results: Both in the total number of patients overall and in the patients with EDSS score <3, tear ET-1 levels were higher in the MS group than that in the controls (p<0.001). In the MS group, the ET-1 level was higher in the patients with EDSS score ≥3 than in those with EDSS score <3 (p<0.001). The tear ET-1 level was positively correlated with age and EDSS score in the MS group (p<0.001). Conclusion: To the best of our knowledge, there is no study in the literature that measures tear ET-1 levels in MS and examines their relationship with EDSS score and VEP. Higher tear ET-1 levels seem to be associated with disability and abnormal VEP in MS. Tear ET-1 measurement may be a simple new noninvasive marker indicating the disability in the patients with MS in the future.

Reactive Oxygen Species Mitigate Perturbations in Coronary Microvascular Tone in Exercising Swine with Multiple Risk Factors

Multiple cardiovascular risk factors, such as diabetes mellitus (DM), chronic kidney disease (CKD) and dyslipidemia are known to induce inflammation and microvascular dysfunction contributing to impaired myocardial perfusion. We previously observed that a combination of DM, high fat diet (HFD) and CKD produced an increase in coronary microvascular tone in awake swine, resulting in perturbations in myocardial O 2 balance. The increased microvascular tone was mediated by an impaired NO bioavailability and was accompanied by increased myocardial levels of reactive oxygen species (ROS) and increased circulating levels of endothelin (ET). In the present study in swine, we tested the hypothesis that ROS scavenging and ET receptor blockade reduce coronary microvascular tone, improving myocardial O 2 delivery and O 2 balance in swine with DM+HFD+CKD. DM (streptozotocin), HFD and CKD (renal artery embolization) were induced in 13 female swine (DM+HFD+CKD), while 11 healthy female swine on normal pig chow served as controls (Normal). After 6 months, the effects of ROS scavenging and ET receptor blockade on coronary microvascular tone were studied at rest and during graded treadmill exercise. 6 months of sustained hyperglycemia (18.1±1.0 in DM+HFD+CKD vs 8.5±0.6 mmol/l in Normal), hypercholesterolemia (12.3±2.0 vs 1.7±0.1 mmol/l) and renal dysfunction (plasma creatinine: 165±7 vs 119±3 μmol/l) were accompanied by systemic inflammation (TNF 52±5 vs 25±6 pg/ml), elevated ET plasma levels, (36±2 vs 29±2 pg/ml), and oxidative stress (myocardial PGF2α 12.9±0.8 vs 10.2±0.5 pg/mg protein, all P<0.05 by t-test). Surprisingly, i n vivo ROS scavenging (TEMPOL+MPG) reduced myocardial O 2 delivery (forcing an increased myocardial O 2 extraction) in DM+HFD+CKD swine, indicative of a coronary microvascular constrictor response to ROS scavenging, implying a ROS-mediated vasodilator influence. In vitro experiments, using catalase in coronary small arteries, suggested a vasodilator role for hydrogen peroxide (H 2 O 2 ) in DM+HFD+CKD but not in Normal swine. A switch from NO towards to H 2 O 2 in the regulation of coronary microvascular tone was further supported by an increase in ceramide production (138±34 vs 45±4 nmol/ml, P<0.05) and increased activity of catalase in the myocardium (44±3 vs 31±4 nmol/min/mg, P<0.05) of DM+HFD+CKD vs Normal swine. Despite elevated ET plasma levels in DM+HFD+CKD swine, combined ET A /ET B receptor blockade with tezosentan did not affect myocardial O 2 balance in either Normal or DM+HFD+CKD swine. Conclusion: In swine, 6 months exposure to multiple risk factors resulted in increased oxidative stress that paradoxically acted to mitigate perturbations in coronary microvascular tone via an H 2 O 2 -mediated coronary vasodilator influence. Despite an increase in circulating ET levels, we found no evidence for an increased ET mediated coronary vasoconstrictor influence. Funding: Grants 2017B018 ARENA-PRIME and 2020B008 RECONNEXT This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 245: Endothelin-1 And Procollagen Type-1 Carboxy-terminal Propeptide Are Associated With Functional Tolerance And Cardiac Structure And Function In Heart Failure With Preserved Ejection Fraction

Introduction: The role of emerging biomarkers such as endothelin-1 (ET-1) and collagen peptides in functional tolerance among patients with heart failure with preserved ejection fraction (HFpEF) is not well understood. Hypothesis: We hypothesize that plasma ET-1 and procollagen type-1 carboxy-terminal propeptide (PICP) are associated with 6-minute walk distance and parameters of cardiac structure and function. Methods: In a cross-sectional cohort study, we evaluated the association of ET-1 and PICP with 6-minute walk distance and parameters of cardiac structure and function on cardiac magnetic resonance (CMR) imaging in patients with HFpEF. In a subset of patients, we used a novel diffusion tensor imaging CMR technique to determine the myocardial fiber orientation in the septum as characterized by the helix angle transmurality (slope of the helix angle versus transmural depth from endocardium to epicardium) (Fig 1C). Results: A total of 36 patients (25 with HFpEF, 11 controls), mean age 70 ± 7.7 yrs, BMI 33 ± 8.5 kg/m 2 , 94% men, 53% had diabetes, and 75% had hypertension. Mean LVEF 58.7 ± 7.7%, RVEF 49.1 ± 10.4%, mean global myocardial mid- LV T1 1285ms, mean LV mass indexed to body surface area 65 ± 12 g/m 2 . Using univariate linear regression, we found that both plasma ET-1 levels and PICP levels were moderately inversely associated with 6-minute walk distance (R 2 -0.56, p<0.001) and (R 2 -0.40, p=0.02) (Fig 1A) respectively, with a non-significant association with age (R 2 = 0.30, p=0.08) and indexed LV mass (R 2 =0.29, p=0.09). ET-1 was moderately associated with septal HAT, a marker of myocardial fiber orientation, (R 2 =0.58, p=0.02), measured in a subset of patients (Fig 1B, C). Conclusions: Plasma ET1 and PICP levels are moderately associated with lower 6-minute walk distance; ET-1 is associated with septal myocardial fiber orientation in this exploratory analysis. Future studies are needed to determine the prognostic value of these biomarkers in patients with HFpEF.

Antihypertensive effects of Pleurospermum lindleyanum aqueous extract in spontaneously hypertensive rats.

Pleurospermum lindleyanum (Lipsky) B. Fedtsch is a perennial herb classified in the Apiaceae family, genus Pleurospermum, chiefly native to the Taxkorgan County, Xinjiang, China. In the Xinjiang Province, it is a well-known ethnic traditional herb, often addressed by its tribal name, Kurumuti. It grows in harsh conditions over 4000m above sea level, such as the Pamirs plateau. It is rich in flavonoids, coumarins, terpenoids, essential oil, substances that have been widely applied in the prevention and treatment of hypertension, diabetes, coronary heart disease, and cerebral thrombosis by local Tajik residents. The present study aimed to evaluate the antihypertensive effects of the Pleurospermum Lindleyanum aqueous extract (PLAE) in spontaneously hypertensive rats (SHRs). The Pleurospermum lindleyanum was collected from the Taxkorgan Tajik Autonomous County, Xinjiang, China. The main chemical composition of PLAE was identified using the ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). SHRs were treated by gavage with PLAE (equivalent to Pleurospermum lindleyanum 5 or 10g/kg/day) for 6 weeks, using Captopril (10mg/kg/day) as positive control. The systolic blood pressure (SBP), renal and cardiac morphology, plasma levels of angiotensin-converting enzyme (ACE), aldosterone (ALD), angiotensinⅡ (AngⅡ), superoxide dismutase (SOD), endothelin-1 (ET-1) and nitric oxide (NO) were measured. A total of 30 compounds were identified in PLAE. PLAE significantly attenuated the SBP of SHRs. The effects began after 3 weeks of administration and then became steady and long-lasting. Its potential mechanisms may be associated with the protective effects on renal and cardiac injury caused by hypertension, the decrease of plasma vasoconstrictors, such as ACE, ALD, AngⅡ, and ET-1 levels, the maintenance of NO/ET balance, the increase in plasma NO levels and SOD activity, thereby reducing oxidative stress. Pleurospermum lindleyanum can be suggested as a novel antihypertensive ethnic traditional herb, which lays the foundation for researching safe and effective antihypertensive herbal medicines.

Loss of CEACAM1 in endothelial cells causes hepatic fibrosis

ObjectivesHepatocytic CEACAM1 plays a critical role in NASH pathogenesis, as bolstered by the development of insulin resistance, visceral obesity, steatohepatitis and fibrosis in mice with global Ceacam1 (Cc1) deletion. In contrast, VECadCre+Cc1fl/fl mice with endothelial loss of Cc1 manifested insulin sensitivity with no visceral obesity despite elevated NF-κB signaling and increased systemic inflammation. We herein investigated whether VECadCre+Cc1fl/fl male mice develop hepatic fibrosis and whether this is mediated by increased production of endothelin1 (ET1), a transcriptional NF-κB target. MethodsVECadCre+Et1.Cc1fl/fl mice with combined endothelial loss of Cc1/Et1 genes were generated. Histological and immunohistochemical analyses were conducted on their livers and on liver tissue biopsies from adult patients undergoing bariatric surgery or from patients with NASH diagnosis receiving liver transplant. ResultsHepatic fibrosis and inflammatory infiltration developed in VECadCre+Cc1fl/fl liver parenchyma. This was preceded by increased ET1 production and reversed with combined endothelial loss of Et1. Conditioned media from VECadCre+Cc1fl/fl, but not VECadCre+Et1.Cc1fl/fl primary liver endothelial cells activated wild-type hepatic stellate cells; a process inhibited by bosentan, an ETAR/ETBR dual antagonist. Consistently, immunohistochemical analysis of liver biopsies from patients with NASH showed a decline in endothelial CEACAM1 in parallel with increased plasma endothelin1 levels and progression of hepatic fibrosis stage. ConclusionsThe data demonstrated that endothelial CEACAM1 plays a key role in preventing hepatic fibrogenesis by reducing autocrine endothelin1 production.

Effects of Long-Term Intervention with Losartan, Aspirin and Atorvastatin on Vascular Remodeling in Juvenile Spontaneously Hypertensive Rats

Hypertension in adolescents is associated with adverse cardiac and vascular events. In addition to lowering blood pressure, it is not clear whether pharmacological therapy in early life can improve vascular remodeling. This study aimed to evaluate the effects of long-term administration of losartan, aspirin, and atorvastatin on vascular remodeling in juvenile spontaneously hypertensive rats (SHRs). Losartan, aspirin, and atorvastatin were administered via gavage at doses of 20, 10, and 10 mg/kg/day, respectively, on SHRs aged 6-22 weeks. Paraffin sections of the blood vessels were stained with hematoxylin-eosin (H&E) and Sirius Red to evaluate the changes in the vascular structure and the accumulation of different types of collagen. The plasma levels of renin, angiotensin II (Ang II), aldosterone (ALD), endothelin-1 (ET-1), interleukin-6 (IL-6), and neutrophil elastase (NE) were determined using ELISA kits. After the 16-week treatment with losartan, aspirin, and atorvastatin, the wall thickness of the thoracic aorta and carotid artery decreased. The integrity of the elastic fibers in the tunica media was maintained in an orderly manner, and collagen deposition in the adventitia was retarded. The plasma levels of renin, ALD, ET-1, IL-6, and NE in the SHRs also decreased. These findings suggest that losartan, aspirin, and atorvastatin could improve vascular remodeling beyond their antihypertensive, anti-inflammatory, and lipid-lowering effects. Many aspects of the protection provided by pharmacological therapy are important for the prevention of cardiovascular diseases in adults and older adults.

The Effects of Regulating Increased Blood Glucose Levels on Plasma Endothelin-1 Levels After Severe Head Trauma in Rats.

To examine the effects of regulating increased blood glucose levels on plasma ET-1 levels after severe head trauma in rats. Traumatic diffuse brain injury-induced rats were followed for 7 days and were randomly divided into two groups of 36 rats. Pre- and posttraumatic blood glucose and ET-1 levels were measured in group 1 (control). Posttraumatic blood glucose levels were maintained at normal levels using insulin and both blood glucose and ET-1 levels were measured at 2, 6, 12, 24, and 48 h and 7 days posttrauma in group 2. The study excluded animals that died and had skull fractures. Posttraumatic plasma ET-1 levels (n=36) were significantly higher than baseline values in group 1 (p < 0.05). ET-1 levels in group 2 at the 7-day follow-up after trauma were significantly higher than baseline values (n=36) (p < 0.05). However, the increased ET-1 levels were statistically significantly lower in group 2 than in group 1 (p < 0.05). The increased ET-1 levels were significantly prevented by keeping blood glucose levels within normal limits with insulin after severe head trauma. Thus, secondary injury to cerebral blood flow can be prevented by reducing the occurrence of vasospasm that starts in the early posttraumatic period or by stimulating the release of nitric oxide. Therefore, further studies on the role of ET-1 and insulin in developing secondary injuries after severe head trauma would be beneficial.

Clinical value of flow-mediated dilatation of brachial artery in hypertensive disorders complicating pregnancy.

Hypertensive disorders complicating pregnancy (HDCP) are common pregnancy-related disorders. In this study, we aimed to study the clinical value of flow-mediated dilation (FMD) in HDCP and its association with endothelial dysfunction and HDCP-related factors. 160 HDCP patients and 120 healthy pregnancies were enrolled in the study. The expressions of endothelial function markers and FMD were determined. In addition, their correlations in HDCP patients were also analyzed using Pearson's correlation analysis. FMD value decreased gradually from normal pregnancy to severe PE. The levels of plasma nitric oxidase (NO) were significantly lower in the HDCP group than those in the control group, while the levels of plasma endothelin-1 (ET-1) were increased dramatically in the HDCP group. Moreover, the levels of placental growth factor (PLGF) in HDCP women were significantly lower, while the soluble FMS-like tyrosine kinase 1 (sFLt-1) levels were markedly higher than those in control. In addition, the FMD value was correlated with the levels of plasma NO, ET-1, PLGF and sFlt1. It was also found that lower levels of FMD correspond to endothelial dysfunction and abnormal concentrations of PLGF and sFlt-1. The FMD value was associated with endothelial function indicators and could be a strong and non-invasive measure to predict HDCP. The association between the FMD values and endothelial function indicators in HDCP could be helpful for the prediction of pregnant hypertension more accurately.

Xuebijing Administration Alleviates Pulmonary Endothelial Inflammation and Coagulation Dysregulation in the Early Phase of Sepsis in Rats.

Xuebijing injection is a Chinese herbal-derived drug composed of radix paeoniaerubra, rhizomachuanxiong, Salvia miltiorrhiza, floscarthami, and Angelica sinensis. This study aimed to investigate the effects of Xuebijing administration on pulmonary endothelial injury and coagulation dysfunction in a cecal ligation and puncture (CLP)-induced sepsis rat model. A CLP-induced sepsis rat model was established. The CLP rats were treated with a vehicle or Xuebijing via intravenous infusion and sacrificed at 2, 4, 6, 8, or 12 h after CLP for lung tissue and blood sample collection. The mean arterial pressure (MAP) was monitored. Transmission microscopy examination and H&E staining were performed to observe pulmonary structural alterations. Enzyme linked immunosorbent assay (ELISA) was performed to measure the plasma levels of epithelial markers, proinflammatory cytokines, and coagulation-related proteins. Compared with vehicle treatment, Xuebijing administration maintained the MAP in the normal range until 11 h after CLP. Transmission microscopy and H&E staining revealed that Xuebijing administration alleviated alveolar-capillary barrier impairments and lung inflammation in CLP rats. ELISA showed that Xuebijing administration effectively reversed CLP-induced elevations in the plasma levels of epithelial markers endothelin-1 and von Willebrand factor, starting 6 and 8 h after CLP, respectively. Xuebijing administration also significantly abolished CLP-induced rises in circulating proinflammatory cytokines interleukin 6 (IL-6) at 6 h after CLP, IL-1β at 2 and 12 h after CLP, and TNF-α at 2, 4, 6, 8, and 12 h after CLP. In addition, Xuebijing administration strongly reversed CLP-induced alterations in circulating active protein C and tissue-type plasminogen activator, starting 4 h and 2 h after CLP, respectively. Xuebijing ameliorates pulmonary endothelial injury, systemic inflammation, and coagulation dysfunction in early sepsis.

Hydrogen sulfide and miR21 are suitable biomarkers of hypoxic exposure.

Hypoxia is the reduction of alveolar partial pressure of oxygen ([Formula: see text]). Military members and people who practice recreational activities from moderate to high altitudes are at risk for hypoxic exposure. Hypoxemia's signs and symptoms vary from asymptomatic to severe responses, such as excessive hypoxic ventilatory responses and residual neurobehavioral impairment. Therefore, it is essential to identify hypoxia-induced biomarkers to indicate people with exposure to hypoxia. Advances have been made in understanding physiological responses to hypoxia, including elevations in circulating levels of endothelin 1 (ET-1) and microRNA 21 (miR-21) and reduction in circulating levels of hydrogen sulfide (H2S). Although the levels of these factors change upon exposure to hypoxia, it is unclear if these changes are sustained on return to normoxia. We hypothesize that hypoxia-induced ET-1 and miR-21 remain elevated, whereas hypoxia-reduction in H2S sustains after returning to normoxic conditions. To test this hypothesis, we exposed male rats to 6 h of 12% O2 and measured circulating levels of ET-1 and miR-21, pre, during, and posthypoxia. We found that ET-1 plasma levels increased in response to hypoxia but returned to normal levels within 30 min after the restoration of normoxia. miR-21 plasma levels and transdermal H2S emissions decreased in response to hypoxia, remaining decreased on return to normoxia, thus following the biomarker criteria. Therefore, this study supports a unique role for plasma miR21 and transdermal H2S as hypoxia biomarkers that could be used to identify individuals after exposure to hypoxia.

The EDN1 Missense Variant rs5370G > T Regulates Adaptation and Maladaptation under Hypobaric Hypoxia.

Endothelin 1 (EDN1) encodes a potent endogenous vasoconstrictor, ET1, to maintain vascular homeostasis and redistribution of tissue blood flow during exercise. One of the EDN1 missense polymorphisms, rs5370 G/T, has strongly been associated with cardiopulmonary diseases. This study investigated the impact of rs5370 polymorphism in high-altitude pulmonary oedema (HAPE) disorder or maladaptation and adaptation physiology in a well-characterized case–control study of high-altitude and low-altitude populations comprising 310 samples each of HAPE-patients, HAPE-free controls and native highlanders. The rs5370 polymorphism was genotyped, and the gene expression and plasma level of EDN1 were evaluated. The functional relevance of each allele was investigated in the human embryonic kidney 293 cell line after exposure to hypoxia and computationally. The T allele was significantly more prevalent in HAPE-p compared to HAPE-f and HLs. The EDN1 gene expression and ET1 bio-level were significantly elevated in HAPE-p compared to controls. Compared to the G allele, the T allele was significantly associated with elevated levels of ET-1 in all three study groups and cells exposed to hypoxia. The in silico studies further confirmed the stabilizing effect of the T allele on the structural integrity and function of ET1 protein. The ET1 rs5370 T allele is associated with an increased concentration of ET-1 in vivo and in vitro, establishing it as a potent marker in the adaptation/maladaptation physiology under the high-altitude environment. This could also be pertinent in endurance exercises at high altitudes.

Curative Effect of Yangxin Dingji Capsule Combined With Mexiletine Hydrochloride on Postoperative Arrhythmia and Its Influences on the Vascular Endothelial Function in Coronary Bifurcation Lesions.

Objective The aim of the study is to explore the curative effect of Yangxin Dingji capsule combined with mexiletine hydrochloride on postoperative ventricular arrhythmia (VA) and its influences on vascular endothelial function in coronary bifurcation lesions (CBL). Methods A total of 110 patients with CBL admitted to the hospital were enrolled as research subjects between January and December 2021. According to the random number table method, they were divided into a combination group and control group, with 55 cases in each group. The control group was treated with mexiletine hydrochloride, while the combination group was additionally treated with Yangxin Dingji capsules. All were continuously treated for 4 weeks. The clinical response rate between the two groups was compared. The frequencies of 24 h paroxysmal atrial fibrillation, premature atrial contraction, and premature ventricular contraction were compared by the Holter monitoring. The whole blood low-shear viscosity, whole blood high-shear viscosity, and fibrinogen (Fb) in both groups were measured by a full-automatic blood flow analyzer. The levels of plasma nitric oxide (NO), endothelin-1 (ET-1), and von Willebrand factor (vWF) were detected by the nitrate reductase method and enzyme-linked immunosorbent assay (ELISA). During treatment, the occurrence of adverse reactions (vomiting, loss of appetite, dry mouth, diarrhea, nausea) in both groups was statistically analyzed. Results After treatment, the total response rate of treatment in the combination group was significantly higher than that in the control group (P < 0.05). After treatment, frequencies of paroxysmal atrial fibrillation, premature atrial contraction, and premature ventricular contraction in the combination group were significantly lower than those in the control group (P < 0.05). Whole blood low-shear viscosity, whole blood high-shear viscosity, and the Fb level were significantly lower than those in the control group (P < 0.05). After treatment, the NO level in the combination group was significantly higher than that in the control group (P < 0.05), while levels of ET-1 and vWF were significantly lower than those in the control group (P < 0.05). During treatment, there was no significant difference in the total incidence of adverse reactions between the two groups (P > 0.05). Conclusion Yangxin Dingji capsule combined with mexiletine hydrochloride can significantly improve clinical effects in CBL patients, improve VA and vascular endothelial function, and reduce plasma viscosity without increasing the incidence of adverse reactions.

Hydroxychloroquine reduces hypertension and soluble fms-like kinase-1 in a Nω-nitro-l-arginine methyl ester-induced preeclampsia rat model.

Hydroxychloroquine, a drug used for malaria and autoimmune diseases reportedly has beneficial effects against preeclampsia in pregnant women with lupus. However, its mechanism against preeclampsia remains unclear. We investigated the effect of hydroxychloroquine on an Nω-nitro-l-arginine methyl ester-induced preeclampsia rat model. Pregnant Sprague-Dawley rats were divided into four groups based on treatment (administered on gestational days 7-18): control, Nω-nitro-l-arginine methyl ester, hydroxychloroquine, and Nω-nitro-l-arginine methyl ester plus hydroxychloroquine. All animals were sacrificed on gestational day 19. We assayed tube formation and determined reactive oxygen species levels using human umbilical vein endothelial cells. Results showed that hydroxychloroquine significantly lowered mean systolic blood pressure (P < 0.05) in Nω-nitro-l-arginine methyl ester-treated rats. Hydroxychloroquine did not affect their fetal and placental weights. Hydroxychloroquine mitigated Nω-nitro-l-arginine methyl ester-associated changes in proteinuria (P < 0.05). It normalized plasma soluble fms-like kinase-1 (P < 0.05) and endothelin-1 (P < 0.01) levels. In the tube formation assay, hydroxychloroquine increased the total meshes area (P < 0.05) and mitigated Nω-nitro-l-arginine methyl ester-induced reactive oxygen species formation (P < 0.05) in human umbilical vein endothelial cells. We conclude that hydroxychloroquine alleviated hypertension, proteinuria, and normalized soluble fms-like kinase-1 and endothelin-1 levels in our preeclampsia model and that these changes may involve the restoration of endothelial dysfunction; thus, hydroxychloroquine could potentially be used for preventing preeclampsia, even in the absence of lupus.

Efficacy of catgut-embedding therapy at “five neck points” on cervical spondylotic arteriopathy and effects on hemodynamics: A randomized clinical trial “颈五针”穴位埋线治疗椎动脉型颈椎病疗效及对血流动力学的影响-随机临床试验

ObjectiveTo observe the effect of catgut-embedding therapy at five neck points in the treatment of cervical spondylotic arteriopathy (CSA) and analyze its effects on the hemodynamics of patients with CSA. MethodsUsing the computer randomization method, 72 patients with CSA were divided into a catgut-embedding therapy group (n = 36, none dropped out) and a western medication group (n = 36, none dropped out). In the catgut-embedding therapy group, the therapy was applied to five neck points, i.e. bilateral Jĭngjiājĭ (颈夹脊) at C5, bilateral Jĭngjiājĭ (颈夹脊) at C6, and Dàzhuī (大椎GV14) once a week. One 3-week treatment session was required. In the western medication group, flunarizine hydrochloride 5 mg capsules were administered orally once daily for 3 weeks. Efficacy was assessed before and after 3 weeks treatment using a functional evaluation scale for cervical spondylotic arteriopathy (FS-CSA). Changes in vertebral-basilar arterial hemodynamics, serum nitric oxide (NO) level, and plasma endothelin (ET) level were detected. ResultsEfficacy was assessed when the treatment session was completed. The total efficacy rate was significantly higher in the catgut-embedding therapy group (86.1%) than in the western medication group (61.1%; P < 0.01). The after treatment FS-CSA score was reduced compared with baseline score in both groups (P < 0.05), and the reduction in the catgut-embedding therapy group was superior to that in the Western medication group (P < 0.05). Compared with baseline, the flow velocity and pulsatility index of the bilateral vertebral and basilar arteries increased at each period in both groups (P < 0.05) except for the left systolic velocity of the vertebral artery after treatment. The increase in the catgut-embedding therapy group was greater than that in the western medication group (P < 0.05). After treatment, the serum NO concentration was increased and the plasma ET concentration was reduced compared to baseline in both groups (P < 0.05), while the improvements in the catgut-embedding therapy group were superior to those in the western medication group (P < 0.05). ConclusionThe clinical efficacy in the catgut-embedding therapy group was superior to that in the western medication group. Catgut-embedding therapy at five neck points may effectively improve psychological and functional conditions, promote vertebral basilar arterial supply, and relieve clinical symptoms in patients with CSA.