Talya Wolak

Tomato extract and the carotenoids lycopene and lutein improve endothelial function and attenuate inflammatory NF-κB signaling in endothelial cells.

Objectives: In our previous research the antihypertensive properties of lycopene-containing tomato oleoresin have been revealed. The present study was aimed to assess if oleoresin interferes in the inflammatory signalling in endothelial cells, imitating reduction of inflammatory processes in the vessel wall and in this way to propose the mechanism for the reduction of blood pressure by oleoresin. Methods and results: A wide number of functional and inflammatory markers were investigated in two cultured endothelial cell models [EA.hy926 and human umbilical vein endothelial cell (HUVEC)], exposed to oleoresin and carotenoids lycopene and lutein. All the carotenoids significantly improved basic endothelial function as measured by increased nitric oxide and decreased endothelin (ET-1) release. They were effective in attenuation of inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-&kgr;B) signalling: decrease of tumour necrosis factor-alpha (TNF-&agr;)-induced leukocytes adhesion, expression of adhesion molecules inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and nuclear translocation of NF-&kgr;B components as well as some revert of inhibitor of kappa B (I&kgr;B) ubiquitination. In addition, the carotenoids were able to inhibit NF-&kgr;B activation in transfected endothelial cells. When combined with lutein, oleoresin exerted synergistic effect on preclusion of leukocytes adhesion. Conclusions: Prevention of over-expression of adhesion molecules through inhibition of NF-&kgr;B signalling may be one of the main mechanisms driving carotenoids to attenuate inflammatory leukocyte adhesion to endothelium. This is the first profound study on the mechanisms involved in the positive action of natural tomato products in endothelial cells.

Stimulation of NADPH oxidase by angiotensin II in human neutrophils is mediated by ERK, p38 MAP-kinase and cytosolic phospholipase A2.

Objective The present research was designed to study the involvement of ERK and p38 MAP-kinase in cytosolic phospholipase A2 (cPLA2) and NADPH-oxidase activation by angiotensin II (Ang II) in human neutrophils. Methods NADPH-oxidase activity was measured by reduction of cytochrome C. cPLA2 activity was measured in cell lysate using sonicated dispersions of 1-stearoyl-2-[14C]arachidonyl phosphatidylcholine. Cells were incubated with MEK inhibitor UO126 or with p38 MAP-kinase inhibitor SB202190 prior to stimulation with Ang II. Translocation of p47phox, p67phox and cPLA2 and phosphorylation of ERK and p38 MAP-kinase were measured by immunoblot analysis. Results Ang II induced a dose-dependent activation of NADPH oxidase in neutrophils and monocytes as well as in differentiated PLB-985 cells towards neutrophil or monocyte lineages, but not in cPLA2-deficient differentiated PLB-985 cells. An immediate activation of both ERK and p38 MAP-kinase and of cPLA2 was induced by Ang II in human neutrophils. In addition, Ang II induced translocation of the cytosolic oxidase components, detected by translocation of p47phox, which preceded the translocation of cPLA2 induced by this agonist. The p38 MAP-kinase inhibitor SB202190 or the MEK–ERK pathway inhibitor UO126 totally inhibited the activation of both NADPH oxidase and cPLA2 as well as the translocation of cytosolic oxidase components and of cPLA2 to the membrane fractions. Conclusions These results suggest that either ERK or p38 MAP-kinase are involved in the activation of both cPLA2 and NADPH oxidase, and that cPLA2 is required for activation of the NADPH oxidase by Ang II in human neutrophils.

High uric acid level during the first 20 weeks of pregnancy is associated with higher risk for gestational diabetes mellitus and mild preeclampsia.

Objective. To examine the association between uric acid (UA) level during the first 20 weeks of pregnancy and the development of gestational diabetes mellitus (GDM) and preeclampsia in the second half of pregnancy. Methods. The study population included registered births (n = 5507) between 2001 and 2007 in a tertiary medical center. The UA levels during the first 20 weeks of pregnancy were sorted by UA ≤ 2.4 mEq/L; UA = 2.5–4.0 mEq/L, UA = 4.1–5.5 mEq/L, and UA > 5.5 mEq/L. The linear-by-linear chi-square test and ROC curves were used to determine the association between UA level during the first 20 weeks and pregnancy complications. Multivariate analyses were performed to demonstrate whether UA level is an independent factor for the prevalence of preeclampsia and GDM. Results. Significant linear association was documented between UA level in the first 20 weeks and the prevalence of GDM and mild preeclampsia. The lowest and the highest prevalence of GDM were found in the UA ≤ 2.4 mEq/L group (6.3%) and in the UA > 5.5 mEq/L group (10.5%) (p < 0.001), respectively. Mild preeclampsia was diagnosed in 2.1% of the patients from the UA ≤ 2.4 mEq/L group, 3.3% from the UA = 2.5–4.0 mEq/L group, 5.3% from the UA = 4.1–5.5 mEq/L group, and 4.5% from the UA > 5.5 mEq/L group (p < 0.001). Three multiple logistic regression models controlling for maternal age showed that UA level is an independent risk factor for both GDM and mild preeclampsia. Conclusions. UA levels in the highest quartile of the normal range during the first 20 weeks of pregnancy are associated with higher risk for the development of GDM and mild preeclampsia.

Can carotenoids attenuate vascular aging

One of the main manifestations of vascular aging is the development of atherosclerotic lesions. These lesions become unstable and prone to rupture due to the formation of reactive oxygen species (ROS) that are produced by the inflammatory milieu in the atherosclerotic plaque. The carotenoids are a group of red, orange, or yellow pigmented polyisoprenoid hydrocarbons synthesized by prokaryotes and higher plants. Lycopene, lutein, and other carotenoids have anti-oxidant activity that attenuates the inflammatory atherosclerotic process and delays vascular aging. This ability improves endothelial function due to the increase in bioavailability of NO. Carotenoid consumption also improves the metabolic profile, decreasing the incidence of diabetes, lowering LDL levels, and improving blood pressure control. The beneficial metabolic effect is translated to improvement in atherosclerosis, which is characterized by a decrease in carotid intima-media thickness. The favorable anti-atherosclerotic effect of carotenoids was also demonstrated in cross-sectional population studies showing a positive correlation between low carotenoid levels and adverse cardiovascular outcome. However, carotenoid utilization failed to decrease major cardiovascular and cerebrovascular events in randomized control double blind trials. The main still unanswered question is: What is the therapeutic role of carotenoids in atherosclerotic disease? Is their anti-atherosclerotic effect restricted to primary prevention or can it alter the prognosis of existing cardiovascular and cerebrovascular diseases?

N-Terminal Rather Than Full-Length Osteopontin or Its C-Terminal Fragment Is Associated With Carotid-Plaque Inflammation in Hypertensive Patients

BACKGROUND Hypertensive patients develop carotid atherosclerotic plaques with enhanced inflammation. Full-length osteopontin (OPN-FL), a multifunctional protein whose levels are elevated in association with atherosclerosis, is cleaved by thrombin and matrix metalloproteinases to form a C-terminal and a putatively biologically active N-terminal fragment (OPN-C, OPN-N, respectively). We conducted a study to examine whether plaque inflammation in hypertensive patients corresponds to the expression of OPN or of its cleaved forms or both. METHODS We collected 42 carotid plaques from 41 consecutive hypertensive patients during carotid endarterectomy. Plaque tissue was used to measure matrix metalloproteinase-12 (MMP-12) and OPN proteins, and for the classification of plaques as showing low- or high-degree inflammation through histological and immunohistochemical evaluation. RESULTS Fifteen highly inflamed plaques and 27 plaques with characteristics of low-grade inflammation were collected. Moderate to heavy staining for OPN characterized 87% of the plaques with high-degree inflammation but only 44% of those with low-degree inflammation, corresponding to the percentages of plaques that were heavily stained for the macrophage marker CD68 (93% versus 26%, respectively, P < 0.01). Western blot analysis showed that the abundance of OPN-FL and OPN-C was comparable in the two groups. However, the abundance of OPN-N was significantly greater in the highly inflamed plaques (median, 3.8 (range, 0.8-7.3) vs. median, 0.9 (range, 0.2-1.5); P = 0.017, respectively). The abundance of MMP-12 was significantly greater in the high- than in the low-degree plaque inflammation group (4.8 (range 1.9-8.8) vs. 1.1 (range 0.3-1.4), respectively; P = 0.03). CONCLUSIONS The N-terminal fragment of osteopontin, rather than OPN-FL or OPN-C, is associated with carotid plaque inflammation in hypertensive patients. Future studies should assess whether targeting OPN cleavage could present a new approach to preventing high-risk carotid plaques.

Low potassium level during the first half of pregnancy is associated with lower risk for the development of gestational diabetes mellitus and severe pre-eclampsia

Objective. To examine the association between potassium level during the first half of pregnancy and the development of gestational diabetes mellitus (GDM) and hypertensive disorders in the second half of the pregnancy. Methods. The study population included all registered births between the years 2001–2007. The potassium levels during the first half of pregnancy were sorted by the following groups: K < 3.5 mEq/l; K = 3.5–3.99 mEq/l; and K ≥ 4 mEq/l. The linear by linear χ2-test was used to determine the association between potassium level during the beginning of pregnancy and pregnancy complications. Results. The study population included 8114 deliveries. A significant linear association was documented between potassium level in the first half of the pregnancy and the prevalence of GDM in the second half of the pregnancy: 6.3% in the K < 3.5 mEq/l group, 6.6% in the K = 3.5–3.99 mEq/l group and 8.2% in the K > 4 mEq/l group; (p = 0.008). A statistically significant for lower rates of severe pre-eclampsia was noted between the groups: 0.4% in the K < 3.5 mEq/l group, 0.9% in the K = 3.5–3.99 mEq/l group, 1.3% in the K = 4.0–4.99 mEq/l group and 1.5% in the K ≥ 5 mEq/l group, (p = 0.027). Indeed, K > 5 mEq/l was noted as a significant risk factor for both, severe pre-eclampsia and for GDM. Using two multiple logistic regression models controlling for maternal age, potassium level was noted as an independent risk factor for both GDM and severe pre-eclampsia. Conclusions. High potassium levels during the first half of pregnancy are associated with higher risk for the development of GDM and severe pre-eclampsia.

Can slight glucose intolerance during pregnancy predict future maternal atherosclerotic morbidity

o examine the association between glucose level during pregnancy and the subsequent development of long‐term maternal atherosclerotic morbidity.

Doxazosin to treat hypertension: it's time to take it personally--a retrospective analysis of 19, 495 patients.

Objective: The aim of the current study was to evaluate the effect of &agr; blockers on the cardiac outcomes of hypertensive patients who underwent myocardial perfusion imaging (MPI). Methods: A retrospective analysis of the nuclear cardiology laboratory database was performed. The study group included only hypertensive patients (n = 19 495). The cohort was divided into three groups – a reference group of no &agr;-blocker therapy (n = 17 053), &agr; blockers for benign prostatic hypertrophy (BPH) (n = 1164), and doxazosin for hypertension (HTN) (n = 1258). We used Cox proportional regression models to examine the patient cardiac outcomes (composite of cardiovascular mortality and myocardial infarction) adjusted for the myocardial perfusion study results. The mean age was 65 ± 11.1 years, 55% were men, and the average follow-up was 79.2 ± 37.3 months. Results: In univariate analysis, the doxazosin for HTN group had the highest rate of adverse cardiac events in comparison to the BPH and reference groups (14.1 vs. 11.3% and 8.9%, respectively, P < 0.001). After stratifying for the degree of reversibility of perfusion defect, only individuals with a moderate-to-severe perfusion defect in the doxazosin for HTN group had a significant increase in adverse cardiac events [hazard ratio 1.50 95% confidence interval (1.14–1.98)]. Conclusion: Our data show that doxazosin treatment for HTN is associated with adverse cardiac outcome only among patients with moderate-to-severe ischemia on myocardial perfusion imaging. Doxazosin and other &agr; blockers appear to be safe in the vast majority of patients with a lesser degree of ischemia.

Left Ventricular Geometric Abnormality Screening in Hypertensive Patients Using a Hand-Carried Ultrasound Device

J Clin Hypertens (Greenwich). 2010;12:181–186. ©2010 Wiley Periodicals, Inc.

Malignant hypertension as a presenting symptom of Takayasu arteritis

We present an unusual case of malignant hypertension in a 20-year-old white woman. One week before hospitalization, she experienced occasional abdominal pain and claudication of both legs; otherwise, she had no remarkable medical history, including no history of high blood pressure. The origin of the patients hypertension was renovascular, and the vascular injury was due to vasculitis of the large arteries. The combination of a difference in blood pressure between the patients arms, angiographic findings, elevated erythrocyte sedimentation rate, and lack of markers for specific vasculitis led to the diagnosis of Takayasu arteritis. Surgical intervention was successful.