Mufangji tang ameliorates pulmonary arterial hypertension through improving vascular remodeling,inhibiting inflammatory response and oxidative stress,and inducing apoptosis

Background:Mufangji tang(MFJT)is composed of Ramulus Cinnamomi,Radix Ginseng,Cocculus orbiculatus(Linn.)DC.,and Gypsum.In clinical settings,MFJT has been effectively employed in addressing a range of respiratory disorders,notably including pulmonary arterial hypertension(PAH).However,the mechanism of action of MFJT on PAH remains unknown.Methods:In this study,a monocrotaline-induced PAH rat model was established and treated with MFJT.The therapeutic effects of MFJT on PAH rat model were evaluated.Network pharmacology was conducted to screen the possible targets for MFJT on PAH,and the molecular docking between the main active components and the core targets was carried out.The key targets identified from network pharmacology were tested.Results:Results showed significant therapeutic effects of MFJT on PAH rat model.Analysis of network pharmacology revealed several potential targets related to apoptosis,inflammation,oxidative stress,and vascular remodeling.Molecular docking showed that the key components were well docked with the core targets.Further experimental validation results that MFJT treatment induced apoptosis(downregulated Bcl-2 levels and upregulated Bax levels in lung tissue),inhibited inflammatory response and oxdative stress(decreased the levels of IL-1β,TNF-α,inducible NOS,and malondialdehyde,and increased the levels of endothelial nitric oxide synthase,nitric oxide,glutathione and superoxide dismutase),reduced the proliferation of pulmonary arterial smooth muscle cells(downregulated ET-1 andβ-catenin levels and ERK1/2 phosphorylation,increased GSK3βlevels).Conclusion:Our study revealed MFJT treatment could alleviate PAH in rats via induction of apoptosis,inhibition of inflammation and oxidative stress,and the prevention of vascular remodeling.

Contribution of oxidative stress to pulmonary arterial hypertension

Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI 2 (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure.

Increased Oxidative Stress in Women With Pregnancy-induced Hypertension

Objective To investigate whether pregnancy-induced hypertension （PIH） may increase oxidative stress in women with PIH, and to explore the mechanisms by which PIH may increase oxidative stress and potential free radical damage. Methods Seventy women with PIH and seventy women with uncomplicated normotensive pregnancy （UNP） whose age, nutritional conditions, levels of hemoglobin and albumin were all matched, were enrolled in a randomized controlled trial. Their plasma concentrations of nitric oxide （NO）, vitamin C （VC）, vitamin E （VE）, and β-carotene （β-CAR） as well as their erythrocyte malondialdehyde （MDA）, and activities of superoxide dismutase （SOD）, catalase （CAT） and glutathione peroxidase （GPX） were determined by spcctrophotometry. Results Compared with average values of the above experimental parameters in the women with UNP, the average value of erythrocyte MDA in the women with PIH significantly increased （P〈0.0001）, while the average values of plasma NO, VC, VE, and β-CAR as well as those of erythrocyte SOD, CAT, and GPX in the women with PIH significantly decreased （P〈0.0005-0.0001）. The findings from partial correlation analysis （controlling for age） for 70 women with PIH showed that with elevated systolic blood pressure （SBP） and diastolic blood pressure （DBP）, MDA value gradually increased （P〈0.001）, and NO, VC, VE, β-CAR, SOD, CAT, and GPX values gradually decreased （P〈0.02-0.001）. The findings from reliability analysis for NO, VC, VE, β-CAR, SOD, CAT, GPX, and MDA values used to reflect increased oxidative stress and potential free radical damage in women with PIH showed that the reliability coefficients （alpha, 8 items） = 0.7062, P〈 0.0001, and the standardized item alpha = 0.9116, P〈 0.0001. Conclusion The findings in the present research suggest that pregnancy-induced hypertension can increase oxidative stress and potential free radical damage in women with pregnancy-induced hypertension.

Job Stress, Gene Polymorphism of β_2-AR, and Prevalence of Hypertension

Objective To study the interactive effect of job stress and genetic susceptibility （or gene polymorphism） on hypertension. Methods A cross-sectional epidemiological study was conducted in 452 workers from a thermal power plant in China. Extrinsic effort, occupational reward, and over-commitment were measured. Hypertensive patients were defined by three phases of screening, reexamination, and final diagnosis. β2-AR genotypes and allele frequencies at amino acid positions 16 （β2-AR-16： Arg→Gly） and 27 （β2-AR-27： Gln→Glu） were identified by PCR-RFLE Results Job stress was related with the prevalence of hypertension in males （P〈0.05）, whereas no significant relationship was found in females （P〉0.05）. Differences in genotypes and allele frequencies of the β2-AR-16 were statistically significant between the hypertension and control groups （P〈0.05）, whereas those of β2-AR-27 were not （P〉0.05）. The prevalence of hypertension was higher in individuals carrying Gly16 allele than in those carrying Arg16 allele of the high job stress group （P〈0.01 or 0.05）. Conclusion High job stress and polymorphism of β2-AR-16 have an interactive effect on the prevalence of hypertension in male workers.

Essential hypertension and oxidative stress:New insights

Essential hypertension is a highly prevalent pathological condition that is considered as one of the most relevant cardiovascular risk factors and is an important cause of morbidity and mortality around the world. Despite the fact that mechanisms underlying hypertension are not yet fully elucidated,a large amount of evidence shows that oxidative stress plays a central role in its pathophysiology. Oxidative stress can be defined as an imbalance between oxidant agents,such as superoxide anion,and antioxidant molecules,and leads to a decrease in nitric oxide bioavailability,which is the main factor responsible for maintaining the vascular tone. Several vasoconstrictor peptides,such as angiotensin Ⅱ,endothelin-1 and urotensin Ⅱ,act through their receptors to stimulate the production of reactive oxygen species,by activating enzymes like NADPH oxidase andxanthine oxidase. The knowledge of the mechanism described above has allowed generating new therapeutic strategies against hypertension based on the use of antioxidants agents,including vitamin C and E,N-Acetylcysteine,polyphenols and selenium,among others. These substances have different therapeutic targets,but all represent antioxidant reinforcement. Several clinical trials using antioxidants have been made. The aim of the present review is to provide new insights about the key role of oxidative stress in the pathophysiology of essential hypertension and new clinical attempts to demonstrate the usefulness of antioxidant therapy in the treatment of hypertension.

A prediction of in vivo mechanical stresses in blood vessels using thermal expansion method and its application to hypertension and vascular stenosis

Mechanical stimuli play critical roles in cardiovascular diseases,in which in vivo stresses in blood vessels present a great challenge to predict.Based on the structural-thermal coupled finite element method,we propose a thermal expansion method to estimate stresses in multi-layer blood vessels under healthy and pathological conditions.The proposed method provides a relatively simple and convenient means to predict reliable in vivo mechanical stresses with accurate residual stress.The method is first verified with the opening-up process and the pressure-radius responses for single and multi-layer vessel models.It is then applied to study the stress variation in a human carotid artery at different hypertension stages and in a plaque of vascular stenosis.Our results show that specific or optimal residual stresses exist for different blood pressures,which helps form a homogeneous stress distribution across vessel walls.High elastic shear stress is identified on the shoulder of the plaque,which contributes to the tearing effect in plaque rupture.The present study indicates that the proposed numerical method is a capable and efficient in vivo stress evaluation of patient-specific blood vessels for clinical purposes.

Nitroglycerine effects on portal vein mechanics and oxidative stress in portal hypertension

AIM:Тo examine the effects of nitroglycerine on portal vein haemodynamics and oxidative stress in patients with portal hypertension.METHODS:Thirty healthy controls and 39 patients with clinically verified portal hypertension and increasedvascular resistance participated in the study.Liver di-ameters,portal diameters and portal flow velocities were recorded using color flow imaging/pulsed Doppler detection.Cross-section area,portal flow and index of vascular resistance were calculated.In collected blood samples,superoxide anion radical (O 2-),hydrogen per-oxide (H 2 O 2),index of lipid peroxidation (measured as TBARS) and nitric oxide (NO) as a marker of endothelial response (measured as nitrite-NO 2-) were determined.Time-dependent analysis was performed at basal state and in 10th and 15th min after nitroglycerine (sublingual 0.5 mg) administration.RESULTS:Oxidative stress parameters changed sig-nificantly during the study.H 2 O 2 decreased at the end of study,probably via O 2-mediated disassembling in Haber Weiss and Fenton reaction;O 2-increased signifi-cantly probably due to increased diameter and tension and decreased shear rate level.Consequently O 2-and H 2 O 2 degradation products,like hydroxyl radical,initi-ated lipid peroxidation.Increased blood flow was to some extent lower in patients than in controls due to double paradoxes,flow velocity decreased,shear rate decreased significantly indicating non Newtonian char-acteristics of portal blood flow.CONCLUSION:This pilot study could be a starting point for further investigation and possible implemen-tation of some antioxidants in the treatment of portal hypertension.

Wall shear stress in portal vein of cirrhotic patients with portal hypertension

AIM To investigate wall shear stress(WSS) magnitude and distribution in cirrhotic patients with portal hypertension using computational fluid dynamics. METHODS Idealized portal vein(PV) system models were reconstructed with different angles of the PV-splenic vein(SV) and superior mesenteric vein(SMV)-SV. Patient-specific models were created according to enhanced computed tomography images. WSS was simulated by using a finite-element analyzer, regarding the blood as a Newtonian fluid and the vessel as a rigid wall. Analysis was carried out to compare the WSSin the portal hypertension group with that in healthy controls.RESULTS For the idealized models, WSS in the portal hypertension group(0-10 dyn/cm2) was significantly lower than that in the healthy controls(10-20 dyn/cm2), and low WSS area(0-1 dyn/cm2) only occurred in the left wall of the PV in the portal hypertension group. Different angles of PV-SV and SMV-SV had different effects on the magnitude and distribution of WSS, and low WSS area often occurred in smaller PV-SV angle and larger SMV-SV angle. In the patient-specific models, WSS in the cirrhotic patients with portal hypertension(10.13 ± 1.34 dyn/cm2) was also significantly lower than that in the healthy controls(P < 0.05). Low WSS area often occurred in the junction area of SV and SMV into the PV, in the area of the division of PV into left and right PV, and in the outer wall of the curving SV in the control group. In the cirrhotic patients with portal hypertension, the low WSS area extended to wider levels and the magnitude of WSS reached lower levels, thereby being more prone to disturbed flow occurrence.CONCLUSION Cirrhotic patients with portal hypertension show dramatic hemodynamic changes with lower WSS and greater potential for disturbed flow, representing a possible causative factor of PV thrombosis.

Inflammation and oxidative stress caused might lead to left ventricular diastolic and hypertension by nitric oxide synthase uncoupling systolic dysfunction in patients with

Objective To investigate the role of oxidative stress, inflammation, hypercoagulability and neuroendocrine activation in the transition of hypertensive heart disease to heart failure with preserved ejection fraction （HFPEF）. Methods We performed echocardiography for 112 patients （≥ 60 years old） with normal EF （18 controls and 94 with hypertension）, and determined protein carbonylation （PC）, and tetrahydrobiopterin （BH4）, C-reactive protein （CRP）, interleukin-6 （IL-6）, tumor necrosis factor-α （TNF-α）, fibrinogen, plasminogen activator inhibitor type-I （PAI-I）, von Willebrand factor, chromogranin A （cGA） and B-type natriuretic peptide （BNP） levels from their blood samples. Results We found that 40% （38/94） of the patients with hypertension （HT） had no diastolic dysfunction （HTDD-）, and 60% （56/94） had diastolic dysfunction （HTDD＋）. Compared to the controls, both patient groups had increased PC and BH4, TNF-α, PAI-I and BNP levels, while the HTDD＋ group had elevated cGA and CRP levels. Decreased atrial and longitudinal left ventficular （LV） systolic and diastolic myocardial deformation （strain and strain rate） was demonstrated in both patient groups versus the control. Patients whose LV diastolic function deteriorated during the follow-up had elevated PC and IL-6 level compared to their own baseline values, and to the respective values of patients whose LV diastolic function remained unchanged. Oxidative stress, inflammation, BNP and PAI-I levels inversely correlated with LV systolic, diastolic and atrial function. Conclusions In patients with HT and normal EF, the most common HFPEF precursor condition, oxidative stress and inflammation may be responsible for LV systolic, diastolic and atrial dysfunction, which are important determinants of the transition of liT to HFPEF.

The Association of Psychological Stress Related Cytokines (TNF Alpha, IFN-Gamma) with Essential Hypertension in Ningxia Hui Autonomous Region

The study aimed to explore the association between psychological stress-related cytokines and essential hypertension to provide the theoretical basis for the prevention and control of the essential hypertension. We screened hypertension patients in six communities in Wuzhong City of Ningxia, and chose the healthy people who had lived in the same community for full 5 years as a control group. Finally, we selected 210 pairs of cases and controls randomly, including 108 pairs of Hui and 102 pairs of Han (50% male;age 35 -74). The results showed that the serum TNF alpha levels of hypertension group were higher than the control group (ρ 0.01), and the serum IFN-gamma levels were lower than the control group both in Hui and Han (ρ 0.01). Further analysis showed that the serum TNF alpha level of the Hui hypertension group was higher than the Han hypertension group (ρ 0.01), while the serum IFN-gamma level was lower than Han hypertension group (ρ 0.01). In conclusion, TNF alpha and IFN-gamma were the important related cytokines between psychological stress and hypertension, and taking effective measures to control the level of serum TNF alpha. IFN-gamma may have the vital significance in alleviating or preventing the genesis and development of essential hypertension.

Sang-Yod rice bran hydrolysates alleviate hypertension, endothelial dysfunction, vascular remodeling, and oxidative stress in nitric oxide deficient hypertensive rats

Objective:To evaluate the potential therapeutic effect of Sang-Yod rice bran hydrolysates(SRH)and in combination with lisinopril against hypertension,endothelial dysfunction,vascular remodeling,and oxidative stress in rats with nitric oxide deficiency-induced hypertension.Methods:Hypertension was induced in male Sprague-Dawley rats by administration of a nitric oxide synthase inhibitor,Nω-nitro-L-arginine methyl ester(L-NAME)in drinking water for 6 weeks.Hypertensive rats were administered daily with SRH(500 mg/kg/day),lisinopril(1 mg/kg/day),or the combination of SRH and lisinopril by gastric lavage for the last 3 weeks of L-NAME treatment.Hemodynamic status,vascular reactivity to vasoactive agents,and vascular remodeling were assessed.Blood and aortic tissues were collected for measurements of oxidative stress markers,plasma angiotensin-converting enzyme(ACE)activity,plasma angiotensinⅡ,and protein expression.Results:L-NAME induced remarkable hypertension and severe oxidative stress,and altered contents of smooth muscle cells,elastin,and collagen of the aortic wall.SRH or lisinopril alone reduced blood pressure,restored endothelial function,decreased plasma ACEs and angiotensinⅡlevels,alleviated oxidant markers and glutathione redox status,and restored the vascular structure.The effects were associated with increased expression of endothelial nitric oxide synthase and decreased expression of gp91phox and AT1R expression.The combination of SRH and lisinopril was more effective than monotherapy.Conclusions:SRH alone or in combination with lisinopril exert an antihypertensive effect and improve endothelial function and vascular remodeling through reducing oxidative stress and suppressing elevated renin-angiotensin system.

Establishment of a model for pregnancy-induced hypertension syndrome resulting from cold-stress in rats

Objective: To establish a model for pregnancy-induced hypertension syndrome in rats. Methods: Adult female Wistar rats were randomized into non-pregnant control (NN), non-pregnant cold-stress control (NC), pregnant control (PN) and pregnant cold-stress (PC) groups. The rats of NN and PN groups were put under 25 ℃ and those of NC and PC groups under (4±2)℃ for 4 h every morning respectively in the whole experimental period. The blood pressure, urine protein, body weight, haematocrit, weight of the placenta and weight and length of the fetus were recorded and the histological changes of the placenta and the kidneys were also studied. Results: The blood pressure and urine protein of the rats of the NC and PC groups after 2 weeks of cold-stress were more significantly increased than the rats of the NN and PN groups. In addition, the weight of the placenta and the weight and length of the fetus were more significantly lower in the former than the latter. Obvious changes of anoxia and ischemia were observed in the tissues of the kidneys and every layer of the placenta. Conclusion: Our findings of hypertension syndrome induced with repeated cold-stress in pregnant rats can be applied to illustrate the pathogenesis of pregnancy-induced hypertension syndrome in human beings.

Hypertension and Work Stress among City Hall Workers, Bohicon, Benin

Introduction: In the general population as well as in the workplace, hypertension is one of the main causes of morbidity and mortality in the world. The particularities of hypertension in the world of work remain little studied. The objective of this study was to determine the prevalence and factors associated with hypertension among workers in a town hall in Benin in 2019. Methods: This was a descriptive, analytical cross-sectional study conducted from December 2018 to January 2019. A comprehensive recruitment was conducted. Data were collected during a face-to-face interview, supplemented by measurement of anthropometric parameters and blood pressure as well as a work stress assessment. Frequencies were compared using the chi-square test and Fisher’s test. The significance level was 5%. Results: A total of 86 workers were included. Their mean age was 41.55 ± 9.82 years with a sex ratio of 6.1. The prevalence of hypertension was estimated to be 18.6% [95% CI: 11.96% - 29.75%]. Hypertension was higher in workers under work stress (41.18%) as opposed to non-stressed workers (14.49%) (p = 0.032);in those who were overweight (30.77) as opposed to non-overweight (2.94%) (p Conclusion: Work stress and obesity are modifiable factors associated with hypertension in workers at the Bohicon city hall. These factors deserve to be corrected by occupational health promotion and prevention actions.

Effects of Xintongding and labellol on hemorheology, oxidative stress and inflammatory endothelial factor in patients with gestational hypertension

Objective:To explore the effects of Xintongding and labellol on hemorheology, oxidative stress and inflammatory endothelial factor in patients with gestational hypertension.Methods:104 patients with gestational hypertension admitted to our hospital from March 2016 to January 2018 were selected as the research object. 52 patients in the control group and 52 patients in the observation group were randomly divided into two groups. The control group was treated with Xintongding, while the observation group was treated with Labellol on the basis of the control group. The changes of blood pressure, hemorheology, oxidative stress index and inflammatory endothelial factors were compared and analyzed between the two groups.Results:Before treatment, there were no significant differences in the levels of SBP, DBP, LBV, HBV, PV, FIB, LPO, MDA, SOD, TNF-α, CRP, VEGF and PLGF. After treatment, the levels of SBP, DBP, LBV, HBV, PV, FIB, LPO, MDA, TNF-α and CRP were significantly decreased, while the levels of SOD, VEGF and PLGF were significantly higher than before treatment, and the levels of SBP, DBP, LBV, HBV, PV, FIB, LPO, MDA, TNF-α and CRP in the observation group were significantly lower than those in the control group, and the levels of SOD, VEGF and PLGF were significantly higher than the control group. Conclusions: Xintongding combined with labetalol in the treatment of hypertensive disorder in pregnancy can effectively improve blood pressure, blood rheology and oxidative stress, reduce inflammation and promote angiogenesis, and has clinical significance.

Effect of low-dose aspirin and Danshen injection on hemorheology, vascular endothelial function and oxidative stress in pregnancy-induced hypertension

Objective:To investigate the effect of low dose aspirin and salvia miltiorrhiza injection on hemorrheology, endothelial function and oxidative stress in patients with pregnancy induced hypertension.Methods: One hundred and eighty pregnancy-induced hypertension patients treated in our hospital from April 2015 to November 2016 were selected as study subjects and randomly divided into control group and observation group with 90 cases in each group. The control group was given routine treatment. The observation group was treated with low-dose aspirin plus Salvia miltiorrhiza in the control group. After treatment, blood rheology, vascular endothelial function and oxidative stress were measured in two groups.Results: The levels of MAP and 24 h Upro in both groups were significantly lower than those before treatment. After treatment, the MAP and 24 h Upro levels in the observation group were significantly lower than those in the control group. After treatment, the level of PT was significantly higher than that before treatment, while the level of DD and Fg was significantly lower than that before treatment. Comparing the two groups after treatment showed that the PT level, and the levels of DD and Fg were significantly lower than those in the control group;After treatment, NO levels in both groups were significantly higher than those before treatment, ET-1 and ET-1/NO levels were significantly lower than before treatment, after treatment, ET-1, NO and ET The NO level in the observation group was significantly higher than that in the control group, while ET-1 and ET-1/NO levels were significantly lower than those in the control group;Compared with those before treatment, the levels of SOD in the two groups were significantly increased and MDA significantly decreased after treatment. The SOD and MDA levels in the two groups after treatment showed that the SOD level in the observation group was significantly higher than that in the control group, while MDA level was significantly lower than that of the control group.Conclusion: The combination of low-dose aspirin and Salvia miltiorrhiza injection has significant therapeutic effect on gestational hypertension, and can effectively improve the hemorheological parameters and endothelial function of patients and reduce the oxidative stress injury in patients. It is worth further clinical promotion.

Fetal middle cerebral artery blood flow characteristics of gestational hypertension combined with fetal distress in uterus as well as their correlation with hypoxia

Objective:To study the fetal middle cerebral artery blood flow characteristics of gestational hypertension combined with fetal distress in uterus as well as their correlation with hypoxia. Methods: Puerperae with hypertensive disorders in pregnancy and fetal distress in uterus, puerperae with hypertensive disorders in pregnancy alone and healthy puerperae who gave birth in our hospital between January 2013 and January 2016 were included in group A, group B and group C of the study respectively. At 34-36 weeks of pregnancy, color Doppler ultrasonography was conducted to determine fetal middle cerebral artery blood flow parameters;after childbirth, umbilical arterial blood was collected to determine blood gas analysis parameters, and the placenta tissue was collected to determine oxidative stress and mitochondria damage indexes.Results:Fetal middle cerebral artery S/D, PI and RI of group A were significantly higher than those of group B and group C while umbilical artery pH value and PaO2 as well as HCO3- and BE content were significantly lower than those of group B and group C;fetal middle cerebral artery S/D, PI and RI as well as umbilical artery pH value, PaO2, HCO3- and BE content of group B were not significantly different from those of group C;Nrf2, ARE, NQO1, VitC, SVCT1, SVCT2, ATP, PGC-1α, PGC-1β, NRF1 and NRF2 content in placenta tissue of group A were significantly lower than those of group B and group C while ROS content was significantly higher than those of group B and group C;Nrf2, ARE, NQO1, VitC, SVCT1, SVCT2, ATP, PGC-1α, PGC-1β, NRF1 and NRF2 content in placenta tissue of group B were significantly lower than those of group C while ROS content was significantly higher than that of group C. Fetal middle cerebral artery S/D, PI and RI were negatively correlated with umbilical artery pH value, PaO2, HCO3- and BE content as well as Nrf2, ARE, NQO1, VitC, SVCT1, SVCT2, ATP, PGC-1α, PGC-1β, NRF1 and NRF2 content, and were positively correlated with ROS content.Conclusions:Gestational hypertension combined with fetal distress in uterus can lead to increased fetal middle cerebral artery blood flow resistance and decreased blood perfusion, and the changes of middle cerebral artery blood flow characteristics can assess the degree of hypoxia and oxidative stress damage.

Effects of Endoplasmic Reticulum Stress on Pulmonary Hypertension in Rat Induced by Chronic Hypoxia and Hypercapnia

Objective: To observe the pulmonary vascular remodeling in rats with pulmonary hypertension induced by hypoxia and hypercapnia, and to explore the role of endoplasmic reticulum stress in pulmonary hypertension. Methods: 1) 40 SD rats were randomly divided into four groups: normoxic control group (N), hypoxia hypercapnia group (HH), endoplasmic reticulum stress (ERS) inhibitor 4-phenyl butyric acid group (4-PBA), ERS pathway agonist tunicamycin group (TM). 2) The mean pulmonary arterial pressure (mPAP) and the right ventricular hypertrophy index (RV/(LV + S)) were measured in each group. 3) Identification of pulmonary artery smooth muscle cells (PASMCs) in each group by immunofluorescence α-SMA. 4) Morphological changes of lung tissue and pulmonary artery were observed by electron microscope. 5) The apoptotic index of PASMCs in each group was detected by TUNEL. 6) Reverse transcription polymerase chain reaction (RT-PCR) and Western Blot (WB) were used to detect the expression of ERS related protein and mRNA (GRP78, CHOP, JNK, Caspase-12) in each group. Results: 1) Compared with the N group, the mPAP, RV/(LV + S) and vascular wall area (WA)/total area (TA) value of HH group, 4-PBA group and TM group were increased (P < 0.01), and the vascular lumen area (LA)/TA values, PASMCs apoptosis index were significantly decreased. GRP78, CHOP, JNK, Caspase-12 expression were increased, and the differences were statistically significant. 2) Compared with the HH group, the mPAP, RV/(LV + S) and WA/TA of 4-PBA group were decreased (P < 0.01);the LA/TA value and PASMCs apoptosis index were increased (P < 0.05);and the mRNA and protein expression of CHOP, JNK, Caspase-12 and GRP78 had a significant decrease (P < 0.05). 3) Compared with the HH, the mPAP, RV/(LV + S) and WA/TA of TM group were increased (P P P < 0.01);and? PASMCs apoptotic index was increased (P < 0.01). Meanwhile, the mRNA expression of Caspase-12, CHOP, JNK and GRP78 was increased to varying degrees (P < 0.05), and the protein expression of Caspase-12, CHOP and JNK was also increased significantly (P Conclusion: Hypoxia and hypercapnia induced pulmonary vascular remodeling may be related to the proliferation of PASMCs, and ERS related factors (JNK, Caspase12 and CHOP) are involved in the regulation of hypoxic hypercapnia.

Carvedilol vs. metoprolol: A comparison of effects on endothelial function and oxidative stress in response to acute hyperglycemia in patients with type 2 diabetes and hypertension

Introduction: The GEMINI trial compared the effects of treatment with metoprolol versus carvedilol in patients with type 2 diabetes. Carvedilol demonstrated a more favorable effect on factors associated with the metabolic syndrome than metoprolol. We hypothesize that carvedilol will have additional beneficial effects on markers of inflammation, oxidative stress, and endothelial function than metoprolol. Methods: Twenty subjects were randomized to either carvedilol or metoprolol. Study procedures including assessment of metabolic parameters and endothelial function, while fasting and after a 75 g oral glucose tolerance were conducted at baseline and following 5 months of treatment. Results: Following 5 months of treatment, PAI-1 increased significantly from baseline in the metoprolol group. There were no changes in PAI-1 in the carvedilol group. While not reaching statistical significance, there was a trend toward worsening insulin resistance with metoprolol treatment compared to carvedilol treatment. Flow mediated vasodilation increased in both groups following the 2-hr OGGT during the baseline study. After five months of treatment, there was a non-significant increase in flow-mediated vasodilation under both fasting and post OGTT conditions in the carvedilol group compared to baseline. Conversely, there was no change in fasting flow mediated vasodilation in the metoprolol group. Additionally, metoprolol treatment blunted the increase in flow mediated vasodilation following OGGT compared to baseline (p < 0.05). Conclusion: Treatment with metoprolol was associated with adverse metabolic effects including increases in PAI-1 and trends toward worsening insulin resistance and endothelial function compared to treatment with carvedilol.

Glutamine prevents oxidative stress in a model of portal hypertension

To evaluate the protective effects of glutamine in a model of portal hypertension (PH) induced by partial portal vein ligation (PPVL). METHODSMale Wistar rats were housed in a controlled environment and were allowed access to food and water ad libitum. Twenty-four male Wistar rats were divided into four experimental groups: (1) control group (SO) - rats underwent exploratory laparotomy; (2) control + glutamine group (SO + G) - rats were subjected to laparotomy and were treated intraperitoneally with glutamine; (3) portal hypertension group (PPVL) - rats were subjected to PPVL; and (4) PPVL + glutamine group (PPVL + G) - rats were treated intraperitoneally with glutamine for seven days. Local injuries were determined by evaluating intestinal segments for oxidative stress using lipid peroxidation and the activities of glutathione peroxidase (GPx), endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) after PPVL. RESULTSLipid peroxidation of the membrane was increased in the animals subjected to PH (P < 0.01). However, the group that received glutamine for seven days after the PPVL procedure showed levels of lipid peroxidation similar to those of the control groups (P > 0.05). The activity of the antioxidant enzyme GTx was decreased in the gut of animals subjected to PH compared with that in the control group of animals not subjected to PH (P < 0.01). However, the group that received glutamine for seven days after the PPVL showed similar GTx activity to both the control groups not subjected to PH (P > 0.05). At least 10 random, non-overlapping images of each histological slide with 200 × magnification (44 pixel = 1 μm) were captured. The sum means of all areas, of each group were calculated. The mean areas of eNOS staining for both of the control groups were similar. The PPVL group showed the largest area of staining for eNOS. The PPVL + G group had the second highest amount of staining, but the mean value was much lower than that of the PPVL group (P < 0.01). For iNOS, the control (SO) and control + G (SO + G) groups showed similar areas of staining. The PPVL group contained the largest area of iNOS staining, followed by the PPVL + G group; however, this area was significantly smaller than that of the group that underwent PH without glutamine (P < 0.01). CONCLUSIONTreatment with glutamine prevents gut mucosal injury after PH in rats.

Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.