Risk Factor For Endothelial Dysfunction Research Articles

PD22-11 SUBCLINICAL INFLAMMATION AS A PREDICTOR FOR ERECTILE DYSFUNCTION AFTER BRACHYTHERAPY FOR LOCALIZED PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022PD22-11 SUBCLINICAL INFLAMMATION AS A PREDICTOR FOR ERECTILE DYSFUNCTION AFTER BRACHYTHERAPY FOR LOCALIZED PROSTATE CANCER Laurianne Rita Garabed, Daniel Taussky, Guila Delouya, and Daniel Liberman Laurianne Rita GarabedLaurianne Rita Garabed More articles by this author , Daniel TausskyDaniel Taussky More articles by this author , Guila DelouyaGuila Delouya More articles by this author , and Daniel LibermanDaniel Liberman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002564.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Neutrophil-to-lymphocyte ratio (NLR), a marker for subclinical inflammation, has been previously shown to be associated with erectile dysfunction (ED). Treatment of localized prostate cancer (PCa) is also associated with a greater risk of ED. In this study, we aimed to determine the potential predictive value of the NLR on ED after prostate brachytherapy (PB) for PCa. METHODS: Between July 2005 and January 2021, 842 patients were included in this retrospective study of a prospectively maintained database. ED was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) physician-reported scale. Patient characteristics and erectile function at last follow-up were compared for patients with a baseline NLR<2 and ≥2. Univariate and multivariate analyses were performed to evaluate the predictive value of baseline NLR ≥2 on post-PB ED. RESULTS: Baseline NLR≥2 was found to be a statistically significant predictor of post-PB ED on both univariate (p=0.002) and multivariate analyses (p=0.008). Furthermore, the difference in ED prevalence between the NLR <2 and NLR ≥2 groups became more pronounced with longer follow-up after PB. The ED rate at 5 years post-PB was 43% for the NLR ≥2 group, compared to 29% for the NLR <2 group. CONCLUSIONS: In a large cohort of patients with PCa who underwent PB, it was found that NLR was a predictor of post-treatment ED, even after adjusting for available covariates, including age and known risk factors for endothelial dysfunction. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e408 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Laurianne Rita Garabed More articles by this author Daniel Taussky More articles by this author Guila Delouya More articles by this author Daniel Liberman More articles by this author Expand All Advertisement PDF DownloadLoading ...

The Potential of Dietary Bioactive Compounds against SARS-CoV-2 and COVID-19-Induced Endothelial Dysfunction.

COVID-19 is an endothelial disease. All the major comorbidities that increase the risk for severe SARS-CoV-2 infection and severe COVID-19 including old age, obesity, diabetes, hypertension, respiratory disease, compromised immune system, coronary artery disease or heart failure are associated with dysfunctional endothelium. Genetics and environmental factors (epigenetics) are major risk factors for endothelial dysfunction. Individuals with metabolic syndrome are at increased risk for severe SARS-CoV-2 infection and poor COVID-19 outcomes and higher risk of mortality. Old age is a non-modifiable risk factor. All other risk factors are modifiable. This review also identifies dietary risk factors for endothelial dysfunction. Potential dietary preventions that address endothelial dysfunction and its sequelae may have an important role in preventing SARS-CoV-2 infection severity and are key factors for future research to address. This review presents some dietary bioactives with demonstrated efficacy against dysfunctional endothelial cells. This review also covers dietary bioactives with efficacy against SARS-CoV-2 infection. Dietary bioactive compounds that prevent endothelial dysfunction and its sequelae, especially in the gastrointestinal tract, will result in more effective prevention of SARS-CoV-2 variant infection severity and are key factors for future food research to address.

Effects of endoplasmic reticulum stress, liver function, insulin resistance and vascular endothelial function in patients with nonalcoholic fatty liver disease.

It is aimed to compare whether there are differences in endoplasmic reticulum stress, liver function, insulin resistance, and vascular endothelial function in patients with nonalcoholic fatty liver disease (NAFLD) with and without type 2 diabetes mellitus (T2DM). Forty patients with NAFLD, 38 patients with NAFLD combined with T2DM, and 30 patients with normal liver tissue were selected. They were set as Group A, Group B and Group C respectively. The expression level of glucose-regulated protein 94 (GRP94) and biochemical indicators such as alanine aminotransferase (ALT), free fatty acids (FFA), triglycerides (TG), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), fasting blood glucose (FBG), and fasting insulin (FINS) were measured. Also, the calculation of the homeostatic model assessment for insulin resistance (HOMA-IR) index was performed. The reactive hyperemia index (RHI) was detected to evaluate the vascular endothelial function of patients. The comparison between groups and multi-factor analysis of the influencing factors of RHI was conducted. Compared with Group C, the expressions in Group A and Group B were distinctly enhanced (P <0.05). Also, the expression of GRP94 protein in Group B was distinctly higher than that in Group A (P <0.05). The average optical density values of Groups A, B, and C were 0.327 ± 0.007, 0.350 ± 0.009, and 0.299 ± 0.006, respectively. A comparison between the three groups was performed. The differences had statistical significance (P <0.05). The differences in the TG, ALT, AST, GGT, FINS and HOMA-IR between Group A and Group B had statistical significance (P <0.05). The RHI values of Groups A, B, and C were 1.59 ± 0.23, 1.79 ± 0.32, and 2.05 ± 0.47, respectively. A comparison between the three groups was performed. The differences had statistical significance (P <0.05). FFA, ALT and FBG in patients with NAFLD are risk factors for endothelial dysfunction (P <0.05). The liver damage caused by NAFLD may be related to the expression of GRP94. FFA, ALT and FBG are risk factors for endothelial dysfunction in NAFLD patients.

An observational study of the endothelial dysfunction in type 2 diabetes mellitus and its association with risk factors

Background: Cardiovascular diseases (CVDs) are the major culprit to cause morbidity in type 2 diabetes mellitus (T2DM) patients. Endothelial dysfunction (ED) precedes the progressed stage of CVD presentation. This study aimed to study the risk factors for ED and identify the modifiable factors for risk reduction and provide caution measures. Materials and Methods: This cross-sectional observational study included 100 adult patients with T2DM on oral hypoglycemic drugs or insulin therapy. Based on glycemic control, type 2 diabetic patients were divided into four groups: Group 1 (poor glycemic control and hemoglobin A1C (HbA1c) >9%), Group 2 (fair glycemic control and HbA1c 8%–8.9%), Group 3 (good glycemic control and HbA1C 7–7.9%), and Group 4 (excellent glycemic control, HbA1C <7%). P < 0.05 was considered statistically significant. Results: Overall, significantly higher glycemic levels (fasting blood glucose, postprandial blood glucose, and HbA1c) and lipid derangements (cholesterol, low-density lipoprotein, and triglyceride) were found in patients with ED as compared to those without ED (P < 0.05). Baseline brachial artery diameter (D1) was into three groups, one group with D1 (≤3.6 mm) with mean flow-mediated dilatation (FMD) of 9.07%, Another group of D1 (3.61 mm to ≤4.30 mm) with mean FMD of 5.26%, and the third group with D1 (>4.41 mm) with mean FMD of 4.58%. There was a statistically significant association seen between baseline brachial artery diameter and FMD (P < 0.05). Multivariate linear regression showed that HbA1c and treatment of both Oral hypoglycemic agents (OHA) and insulin were the significant independent factors affecting the ED with OR of 7.566 (P = 0.0003) and 0.013 (P = 0.011), respectively. Conclusion: In diabetics, the risk of ED is increased with worsening levels of lipid profile and glycemia irrespective of the age and duration of the disease.

The effect of direct acting antiviral agents on vascular endothelial function in Egyptian patients with chronic hepatitis C virus infection

Chronic hepatitis C virus (HCV) infection is correlated with cerebrovascular and cardiovascular disease (CVD). This study aimed to assess the effect of treatment with DAAs on vascular endothelial function in cirrhotic and non-cirrhotic HCV infected patients without any CVD risk factors. Fifty chronic HCV genotype 4 infected patients, without cardiovascular risks who have been listed to receive sofosbuvir/daclatasvir with ribavirin combination as triple therapy for 3 months were prospectively recruited. Endothelial dysfunction markers as soluble vascular cell adhesion molecule-1 (sVCAM-1) and Von willebrand factor (vWf) and inflammation marker (IL6) were estimated at baseline and 3 months post the end of therapy (SVR). All patients achieved SVR. VCAM1 level was significantly improved after HCV clearance with DAA in cirrhotic HCV patients (P = 0.002) compared to patients with mild liver fibrosis (P = 0.006). Levels of vWF also decreased significantly in cirrhosis and non-cirrhosis groups after SVR (P < 0.001 and P = 0.011, respectively). Systemic inflammatory marker (IL6) showed significant decrease in cirrhotic patients (P = 0.001). While, IL6 level did not change significantly in non-cirrhotic group (P = 0.061). Also at SVR, noninvasive liver fibrosis indices have been reduced significantly in the two groups (P < 0.001). HCV clearance by new DAA treatment improves the vascular endothelial dysfunction in Egyptian HCV infected patients with different levels of liver fibrosis and with no risk factors for endothelial dysfunction or CVD.

Cardiovascular disease risk factors induce mesenchymal features and senescence in mouse cardiac endothelial cells.

Aging, obesity, hypertension, and physical inactivity are major risk factors for endothelial dysfunction and cardiovascular disease (CVD). We applied fluorescence-activated cell sorting (FACS), RNA sequencing, and bioinformatic methods to investigate the common effects of CVD risk factors in mouse cardiac endothelial cells (ECs). Aging, obesity, and pressure overload all upregulated pathways related to TGF-β signaling and mesenchymal gene expression, inflammation, vascular permeability, oxidative stress, collagen synthesis, and cellular senescence, whereas exercise training attenuated most of the same pathways. We identified collagen chaperone Serpinh1 (also called as Hsp47) to be significantly increased by aging and obesity and repressed by exercise training. Mechanistic studies demonstrated that increased SERPINH1 in human ECs induced mesenchymal properties, while its silencing inhibited collagen deposition. Our data demonstrate that CVD risk factors significantly remodel the transcriptomic landscape of cardiac ECs inducing inflammatory, senescence, and mesenchymal features. SERPINH1 was identified as a potential therapeutic target in ECs.

Endothelial Function in Coronary Arteries from Pneumonia-Infected Pigs

This study investigated whether pneumonia is accompanied with endothelial dysfunction in coronary arteries. The lungs and hearts of normal and Mycoplasma hyopneumoniae-infected pigs (6-month-old females and castrated males) were obtained from a local abattoir, and left anterior descending coronary arteries were isolated from the hearts. Lymphocyte infiltration was observed in the lung tissue of pneumonia-infected pigs (PP). However, the histopathological images of coronary arteries in PP were not different from the images in normal pigs (NP). In organ chamber experiments, endothelium-dependent relaxation of coronary arteries by bradykinin (0.1 nM–0.1 μM) and A23187 (1 nM–1 μM) were identical between PP and NP; the relaxant responses were not different even in the presence of L-NAME (100 μM, nitric oxide synthase inhibitor) alone or in combination with indomethacin (10 μM, cyclooxygenase inhibitor). In addition, the relaxant responses to nitric oxide [sodium nitroprusside (1 nM–10 μM)], hydrogen peroxide (10 μM–1 mM), and 11, 12-epoxyeicosatrienoic acids (30 nM–3 μM), all of which function as endothelium-derived relaxing factors in pig coronary arteries, were also identical between PP and NP. These findings suggest that mycoplasma pneumonia in pigs is not a risk factor for endothelial dysfunction in coronary arteries.

Circulating senescent angiogenic T cells are linked with endothelial dysfunction and systemic inflammation in hypertension.

Objective:Angiogenic T cells (Tang cells), a recently discovered T-cell subset, have been reported involved in the repair of endothelial injury. The purpose of this study was to explore the correlation of immunologic senescence and pro-inflammatory capacity of Tang cells with endothelial dysfunction in hypertensive patients.Methods:Immunological characteristics of Tang cells (CD3+CD31+CXCR4+) from hypertensive patients with or without endothelial dysfunction were elucidated by surface immunophenotyping and intracellular cytokine staining. Endothelial function was measured by flow-mediated dilation (FMD).Results:The frequency of CD28null subset in CD4+ Tang cells was notably elevated in hypertensive patients with endothelial dysfunction, which was negatively associated with FMD. The high frequency of CD28nullCD4+ Tang cells was an independent risk factor of endothelial dysfunction with good diagnostic performance in ROC curve analysis. Immunophenotyping revealed that this specific subset of Tang cells exhibited senescent profile and has low hTERT expression. CD28nullCD4+ Tang cells produced high levels of inflammatory cytokines, IL-6, IFN-γ and TNF-α, and significantly correlated with the systemic inflammation in hypertensive patients with endothelial dysfunction.Conclusion:Collectively, our findings demonstrate for the first time that CD28null subset in CD4+ Tang cells with senescent and pro-inflammatory phenotype is dependently correlated with impaired FMD and systemic inflammation, which might contribute to the immunopathologic mechanism of endothelial dysfunction. Identification of a pathogenic CD4+ Tang-cell subset lacking CD28 may offer opportunities for the evaluation and management of endothelial dysfunction in hypertension.

Non-Criteria Antiphospholipid Antibodies: Risk Factors for Endothelial Dysfunction in Women with Pre-Eclampsia.

The association between unconventional antiphospholipid antibodies and pre-eclampsia in patients without thrombotic manifestations and its relationship with endothelial dysfunction after delivery has been studied poorly. We included 157 pregnant women, 122 of them having developed pre-eclampsia (56 non-severe and 66 severe). The determination of classical and unconventional, as well as pulse wave velocity and ankle-brachial index were performed at three months after delivery. The prevalence of unconventional antiphospholipid antibodies was 22.9% and 54.9% in patients included in control and pre-eclampsia groups, respectively (p = 0.001). The most frequent antiphospholipid antibody was IgM anti-phosphatidylserine/prothrombin in both cohorts. The presence of IgM anti-phosphatidylserine/prothrombin showed an association with the development of pre-eclampsia (OR = 5.4; CI 95% (2.0–14.9), p = 0.001) with an AUC of 0.744 (p < 0.001). Likewise, IgM anti-phosphatidylserine/prothrombin exhibited a positive linear correlation with pulse wave velocity values (rho = 0.830; p < 0.001) and an association with the presence of pulse wave velocity altered values (OR = 1.33; CI95% (1.10–1.59), p = 0.002). With regard to ankle braquial index values, the presence of IgM anti-phosphatidylserine/prothrombin displayed a weak negative correlation (rho = −0.466; p < 0.001) and an association with altered ankle braquial index values (OR = 1.08; CI 95% (1.04–1.13), p < 0.001). In patients who developed preeclampsia, the presence of IgM anti-phosphatidylserine/prothrombin could be associated with endothelial dysfunction, causing alteration of cardiovascular parameters.

Pre-impaired fasting glucose state is a risk factor for endothelial dysfunction: Flow-mediated Dilation Japan (FMD-J) study

IntroductionDiabetes mellitus is associated with endothelial dysfunction. However, there is little information on the relationships of fasting blood glucose (FBG), including high normal blood glucose and impaired fasting glucose (IFG)...

Correction: The Relationship Between the Impairment of Endothelial Function and Thyroid Antibodies in Hashimoto's Thyroiditis Patients with Euthyroidism.

Endothelial dysfunction is the important early step in the development of atherosclerosis. Hypothyroidism caused by Hashimoto’s thyroiditis and other thyroid disease is one of the risk factors of endothelial dysfunction. The present study tried to investigate the endothelial function and its associated factors in Hashimoto thyroiditis with euthyroidism. A total of 95 newly diagnosed Hashimoto’s thyroiditis patients with euthyroidism and 45 healthy controls were studied. Hashimoto’s patients were divided into 3 subgroups namely, single thyroglobulin antibody (TGAb) positive subgroup, single thyroid peroxidase antibody (TPOAb) positive subgroup, and both TGAb and TPOAb positive subgroup. Endothelial function was tested by the reactive hyperemia index (RHI). Hashimoto’s thyroiditis patients had lower RHI than healthy controls (1.73±0.42 vs 1.96±0.51, p<0.05). Hashimoto’s thyroiditis with single TGAb positive patients had higher RHI than single TPOAb positive (1.98±0.57 vs. 1.69±0.33, p<0.05) and TGAB + TPOAb positive patients (1.98±0.57 vs. 1.68±0.42, p<0.05). RHI were negatively associated with total cholesterol (TC, r=−0.215, p<0.05), low density lipoprotein cholesterol (LDL-C, r=−0.268, p<0.05), triglyceride (TG, r=−0.192, p<0.05), and TPOAb (r=−0.288, p<0.05). In the regression analysis, LDL-C (β=−0.146, p<0.05), TG (β=−0.034, p<0.05) and TPOAb (β=−0.001, p<0.05) were independently associated with RHI. Hashimoto’s patients had poor endothelial function. TPOAb levels were negatively associated with endothelial function.

The Relationship Between the Impairment of Endothelial Function and Thyroid Antibodies in Hashimoto's Thyroiditis Patients with Euthyroidism.

Endothelial dysfunction is the important early step in the development of atherosclerosis. Hypothyroidism caused by Hashimoto's thyroiditis and other thyroid disease is one of the risk factors of endothelial dysfunction. The present study tried to investigate the endothelial function and its associated factors in Hashimoto thyroiditis with euthyroidism. A total of 95 newly diagnosed Hashimoto's thyroiditis patients with euthyroidism and 45 healthy controls were studied. Hashimoto's patients were divided into 3 subgroups namely, single thyroglobulin antibody (TGAb) positive subgroup, single thyroid peroxidase antibody (TPOAb) positive subgroup, and both TGAb and TPOAb positive subgroup. Endothelial function was tested by the reactive hyperemia index (RHI). Hashimoto's thyroiditis patients had lower RHI than healthy controls (1.73±0.42 vs 1.96±0.51, p<0.05). Hashimoto's thyroiditis with single TGAb positive patients had higher RHI than single TPOAb positive (1.98±0.57 vs. 1.69±0.33, p<0.05) and TGAB + TPOAb positive patients (1.98±0.57 vs. 1.68±0.42, p<0.05). RHI were negatively associated with total cholesterol (TC, r=-0.215, p<0.05), low density lipoprotein cholesterol (LDL-C, r=-0.268, p<0.05), triglyceride (TG, r=-0.192, p<0.05), and TPOAb (r=-0.288, p<0.05). In the regression analysis, LDL-C (β=-0.146, p<0.05), TG (β=-0.034, p<0.05) and TPOAb (β=-0.001, p<0.05) were independently associated with RHI. Hashimoto's patients had poor endothelial function. TPOAb levels were negatively associated with endothelial function.

Homocysteine metabolism in rats with metabolic syndrome and the impacts of nigella sativa oil on some biochemical parameters

The high level of fructose taken in the diet is one of the reasons for the increased prevalence of metabolic syndrome, which is increasing day by day globally in association with the effects of genetic and environmental factors. In the study, 21 male Sprague-Dawley rats of 220±20 gr body weight were used. The rats were assigned to 3 groups as the control group, metabolic syndrome group, and the group where Nigella sativa oil was administered. The serum homocysteine levels were increased in the metabolic syndrome group compared to the control group but without statistical significance (p&amp;gt;0.05). Homocysteine levels decreased significantly after Nigella sativa oil compared to metabolic syndrome group. LDH (p &amp;lt;0.001) and uric acid (p &amp;lt;0.05) levels which were higher in metabolic syndrome group were decreased in Nigella sativa oil group. Hyperhomocysteinemia is a risk factor for endothelial dysfunction. In our study, the treatment of the metabolic syndrome and regulation of the increased levels of homocysteine with Nigella sativa oil in metabolic syndrome were discussed. Some biochemical parameters and improvements in homocysteine levels with Nigella sativa oil has been identified. In this study, we have concluded that the occurrence of elevated levels of plasma homocysteine are closely associated with the development of inflammation, cellular adhesion, hepatic dysfunction, and cell proliferation and that the reduction in the serum levels of homocysteine by the administration of Nigella sativa oil will lead to favorable out comes.

Trans, trans-2,4-decadienal impairs vascular endothelial function by inducing oxidative/nitrative stress and apoptosis

Aldehydes are implicated in the development of hypertension. Trans, trans-2,4-decadienal (tt-DDE), a dietary α,β-unsaturated aldehyde, is widespread in many food products. However, the role of tt-DDE in the pathophysiology of hypertension remains unknown. This study was designed to investigate whether tt-DDE consumption evokes hypertension and to explore the mechanisms underlying such a role. Sprague-Dawley rats were administered different concentrations of tt-DDE. After 28 days, blood pressure and endothelial function of mesenteric arteries were measured. Results showed that tt-DDE treatment significantly increased blood pressure and impaired endothelial function based on endothelium-dependent vasorelaxation and p-VASP levels. Mechanistically, tt-DDE induced oxidative/nitrative stress in the arteries of rats as evidenced by overproductions of superoxide and peroxynitrite, accompanied with increased expressions of iNOS and gp91phox. To further investigate the effects of tt-DDE on endothelial cells and underlying mechanisms, human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of tt-DDE. tt-DDE induced oxidative/nitrative stress in HUVECs. Moreover, tt-DDE induced endothelial cells apoptosis through JNK-mediated signaling pathway. These results show, for the first time, that oral intake of tt-DDE elevates blood pressure and induces endothelial dysfunction in rats through oxidative/nitrative stress and JNK-mediated apoptosis signaling, indicating that excess ingestion of tt-DDE is a potential risk factor for endothelial dysfunction and hypertension.

H19/TET1 axis promotes TGF-β signaling linked to endothelial-to-mesenchymal transition.

While emerging evidence suggests the link between endothelial activation of TGF‐β signaling, induction of endothelial‐to‐mesenchymal transition (EndMT), and cardiovascular disease (CVD), the molecular underpinning of this connection remains enigmatic. Here, we report aberrant expression of H19 lncRNA and TET1 in endothelial cells (ECs) of human atherosclerotic coronary arteries. Using primary human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells (HAoECs) we show that TNF‐α, a known risk factor for endothelial dysfunction and CVD, induces H19 expression which in turn activates TGF‐β signaling and EndMT via a TET1‐dependent epigenetic mechanism. We also show that H19 regulates TET1 expression at the posttranscriptional level. Further, we provide evidence that this H19/TET1‐mediated regulation of TGF‐β signaling and EndMT occurs in mouse pulmonary microvascular ECs in vivo under hyperglycemic conditions. We propose that endothelial activation of the H19/TET1 axis may play an important role in EndMT and perhaps CVD.

Endothelial Mineralocorticoid Receptor Deletion Abrogates Leptin‐Induced Endothelial Dysfunction in Pregnant Mice

Obesity is a risk factor for endothelial dysfunction and hypertension in pregnancy, both of which are hallmarks of preeclampsia. Our lab has demonstrated that obesity‐associated endothelial dysfunction and hypertension in female mouse models is mediated via leptin‐induced aldosterone production and subsequent mineralocorticoid receptor (MR) activation. We also showed that progesterone increases endothelial MR (ECMR) expression and that high progesterone levels in pregnant mice are associated with highly elevated ECMR expression, potentially rendering pregnant female mice susceptible to leptin‐induced endothelial dysfunction in obese pregnancy. Therefore, we hypothesized that ECMR deletion would prevent leptin‐induced endothelial dysfunction in pregnant mice in late gestation. Endothelial function was experimentally measured by wire myography concentration response curves to acetylcholine in mouse aorta. Chronic leptin infusion (0.9mg/kg/day, s.c. osmotic minipump) throughout late‐gestation (gestational days 11–18) induced endothelial impairment in wild‐type pregnant mice that was impaired both compared to sham‐treated pregnant (2‐way ANOVA with repeated measures, *P&lt;0.05) and non‐pregnant leptin‐infused females (*P&lt;0.05). However, leptin infusion in pregnant ECMR−/− mice did not induce similar endothelial dysfunction (*P&lt;0.05). Relaxation responses to acetylcholine in the presence of LNAME indicated that endothelial dysfunction in pregnant leptin‐infused mice was attributable to reduction in nitric oxide activity. In addition, no changes in endothelial‐independent sodium nitroprusside responses were observed among groups. Placental dysfunction is a characteristic of preeclampsia that precludes the development of endothelial dysfunction and hypertension. In homogenized placentas, mRNA expression of hypoxia‐inducible factor 1α (HIF1α), a marker of ischemia, was increased by leptin infusion in wild‐type (1.9±0.2‐fold change from sham wild‐type, P=0.08), but not in ECMR−/− (1.2±0.2‐fold change from sham ECMR−/−) pregnant mice. These changes in placental function were associated with adverse fetal effects in leptin‐infused wild‐type mice as indicated by decreased pup weight (0.86±0.04g sham wild‐type vs 0.52±0.11g wild‐type +leptin, *P&lt;0.05). However, ECMR deletion rescued pup weight in leptin‐infused pregnant mice (0.79±0.08g, sham ECMR−/− vs 0.86±0.11g, ECMR−/− +leptin). Collectively, these data indicate that high leptin levels in obese pregnancies may predispose to placental dysfunction and endothelial dysfunction, which are characteristics of preeclampsia.Support or Funding Information1R01HL130301‐01, 19EIA34760167, Adrenal Center pilot grant, 1K99HL146948‐01A1

Serum homocysteine and folate concentrations in early pregnancy and subsequent events of adverse pregnancy outcome: the Sichuan Homocysteine study

BackgroundHyperhomocysteinemia may be a risk factor for endothelial dysfunction. Folate and vitamin B12 regulate the homocysteine metabolic process. This study aimed to evaluate the associations between subsequent events of adverse pregnancy outcome and early variables of homocysteine, folate, and vitamin B12 in pregnant women.MethodsThis multicenter, retrospective, case–control study involved 563 pregnant women with adverse pregnancy outcome and 600 controls. Adverse pregnancy outcomes included one or more of the following events: preeclampsia, preterm birth, low birth weight, and stillbirth. The associations between subsequent events of adverse pregnancy outcome and early variables of homocysteine, folate, and vitamin B12; metabolic parameters; inflammatory markers; anthropometrics; and lifestyle habits at 11–12 weeks of gestation were analyzed using the logistic regression model.ResultsCompared to the lower quartile homocysteine concentrations, the upper quartile homocysteine concentrations were associated with preeclampsia, preterm birth and low birth weight. On the contrary, the lower quartile folate concentrations were associated with preeclampsia, preterm birth and low birth weight compared with the upper quartile folate concentrations. The incidence of adverse pregnancy outcome increased progressively from the first to fourth homocysteine quartiles but decreased progressively from the first to fourth folate quartiles. After adjusting for confounding factors, multivariate logistic regression analysis showed that besides systolic blood pressure, diastolic blood pressure, body mass index and age, homocysteine (IV vs I quartile, aOR 5.89, 95% CI 4.08–8.51, P < 0.001), folate (IV vs I quartile, aOR 0.35, 95% CI 0.25–0.50, P < 0.001), folate supplementation (yes vs no, aOR 0.55, 95% CI 0.35–0.86, P = 0.010) during early pregnancy were independently associated with subsequent events of adverse pregnancy outcome, and vitamin B12 was rejected. Of these, the homocysteine revealed the highest odds ratio in all risk variables, and folate showed the lowest odds ratio in all protective variables.ConclusionsHigher homocysteine concentration and lower folate level during early pregnancy were associated with adverse pregnancy outcome. However, no association was found between vitamin B12 and adverse pregnancy outcome. Supplementation with folate in early pregnancy may reduce adverse pregnancy outcome.

Helicobacter pylori Infection Impairs Endothelial Function Through an Exosome-Mediated Mechanism.

BackgroundEpidemiological studies have suggested an association between Helicobacter pylori (H pylori) infection and atherosclerosis through undefined mechanisms. Endothelial dysfunction is critical to the development of atherosclerosis and related cardiovascular diseases. The present study was designed to test the hypothesis that H pylori infection impaires endothelial function through exosome‐mediated mechanisms.Methods and ResultsYoung male and female patients (18‐35 years old) with and without H pylori infection were recruited to minimize the chance of potential risk factors for endothelial dysfunction for the study. Endothelium‐dependent flow‐mediated vasodilatation of the brachial artery was evaluated in the patients and control subjects. Mouse infection models with CagA+ H pylori from a gastric ulcer patient were created to determine if H pylori infection‐induced endothelial dysfunction could be reproduced in animal models. H pylori infection significantly decreased endothelium‐dependent flow‐mediated vasodilatation in young patients and significantly attenuated acetylcholine‐induced endothelium‐dependent aortic relaxation without change in nitroglycerin‐induced endothelium‐independent vascular relaxation in mice. H pylori eradication significantly improved endothelium‐dependent vasodilation in both patients and mice with H pylori infection. Exosomes from conditioned media of human gastric epithelial cells cultured with CagA+ H pylori or serum exosomes from patients and mice with H pylori infection significantly decreased endothelial functions with decreased migration, tube formation, and proliferation in vitro. Inhibition of exosome secretion with GW4869 effectively preserved endothelial function in mice with H pylori infection.Conclusions H pylori infection impaired endothelial function in patients and mice through exosome‐medicated mechanisms. The findings indicated that H pylori infection might be a novel risk factor for cardiovascular diseases.

Vitamin D and Endothelial Function.

Vitamin D is known to elicit a vasoprotective effect, while vitamin D deficiency is a risk factor for endothelial dysfunction (ED). ED is characterized by reduced bioavailability of a potent endothelium-dependent vasodilator, nitric oxide (NO), and is an early event in the development of atherosclerosis. In endothelial cells, vitamin D regulates NO synthesis by mediating the activity of the endothelial NO synthase (eNOS). Under pathogenic conditions, the oxidative stress caused by excessive production of reactive oxygen species (ROS) facilitates NO degradation and suppresses NO synthesis, consequently reducing NO bioavailability. Vitamin D, however, counteracts the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which produces ROS, and improves antioxidant capacity by enhancing the activity of antioxidative enzymes such as superoxide dismutase. In addition to ROS, proinflammatory mediators such as TNF-α and IL-6 are risk factors for ED, restraining NO and eNOS bioactivity and upregulating the expression of various atherosclerotic factors through the NF-κB pathway. These proinflammatory activities are inhibited by vitamin D by suppressing NF-κB signaling and production of proinflammatory cytokines. In this review, we discuss the diverse activities of vitamin D in regulating NO bioavailability and endothelial function.

The circulating level of miR-122 is a potential risk factor for endothelial dysfunction in young patients with essential hypertension.

MicroRNAs are key molecules involved in the regulation of endothelial function. They are important risk factors and biomarkers for the development of hypertension related to endothelial dysfunction. However, the gene expression patterns associated with hypertension development related to endothelial dysfunction have not been fully elucidated. We conducted a case-control study of 65 patients with essential hypertension (EH) and 61 controls without EH. Plasma levels of miR-122 and its target protein high-affinity cationic amino acid transporter 1 (CAT-1) were measured by qRT-PCR and ELISA, respectively. miR-122 expression in plasma of patients with EH was significantly higher than that of the control group (p = 0.001), while CAT-1 expression in patients with EH was significantly lower than that in the control group (p = 0.018). miR-122 expression in plasma of young patients with EH was significantly higher than that in young people without EH (p = 0.0004), and CAT-1 expression in plasma of young patients with EH was also significantly lower than that of the control group (p = 0.002). CAT-1 expression in the plasma of young participants was significantly higher than that of individuals aged ≥40 years (p = 0.003), whereas miR-122 expression was significantly lower (p = 0.001). We showed that among patients with EH, the high expression of miR-122 contributed to endothelial dysfunction by suppressing the expression of the CAT-1 protein, which led to a decrease in CAT-1 expression in plasma. Therefore, high expression of miR-122 appears to be a risk factor for endothelial dysfunction in EH, especially in younger patients.