bluuebunny/crossref_metadata_2025 huggingface dataset:
Thrombin Causes Vascular Endothelial Growth Factor Expression in Vascular Smooth Muscle Cells
Authors: Bassus Steffen , Herkert Olaf , Kronemann Nicola , Görlach Agnes , Bremerich Dorothee , Kirchmaier Carl M. , Busse Rudi , Schini-Kerth Valérie B.
Published: September 2007

Abstract
—Vascular endothelial growth factor (VEGF) has been implicated in the reendothelialization of the vascular wall after balloon injury. This study investigated whether thrombin, which is formed during activation of the coagulation cascade at sites of vascular injury, upregulates VEGF expression in vascular smooth muscle cells (VSMCs). VEGF expression was assessed in native and cultured VSMCs by Northern blot analysis and reverse transcription–polymerase chain reaction and the release of VEGF protein by immunoassay. α-Thrombin time- and concentration-dependently increased VEGF mRNA levels, mainly that mRNA coding for the soluble splice variant VEGF
164/165
, and stimulated the release of VEGF protein. These effects required the proteolytic activity of thrombin and were mimicked by a thrombin receptor activating–peptide. Upregulation of VEGF expression was also induced by conditioned medium from α-thrombin–stimulated VSMCs. Both the early and the delayed α-thrombin–induced VEGF expressions were attenuated by antioxidants and by diphenyleneiodonium. α-Thrombin–induced VEGF release was significantly reduced by a platelet-derived growth factor (PDGF)–, a transforming growth factor (TGF)-β–, and a basic fibroblast growth factor (bFGF)–neutralizing antibody. Thrombin caused a redox-sensitive upregulation of expression of VEGF in VSMCs through a direct and an indirect effect, which was dependent on the endogenous formation of PDGF, TGF-β, and bFGF. Upregulation of VEGF expression may represent an important mechanism by which the coagulation cascade contributes to the regeneration of the endothelial lining at sites of balloon injury.
Kininostatin, an Angiogenic Inhibitor, Inhibits Proliferation and Induces Apoptosis of Human Endothelial Cells
Authors: Guo Yan-Lin , Wang Shujie , Colman Robert W.
Published: September 2007

We recently reported that domain 5 (D5) of high-molecular-weight kininogen inhibited critical steps required for angiogenesis. Thus, it was named kininostatin. To understand its mechanism of action, we further investigated the effects of D5 on basic fibroblast growth factor (bFGF)-induced endothelial cell proliferation and cell viability. We report here that D5-inhibited cell proliferation of human endothelial cells stimulated by bFGF was associated with a significant reduction of cyclin D1 expression, which is a critical component required for the transition from G
1
to S phase of the cell cycle. However, inhibition of cell proliferation by D5 was not due to an inhibition of extracellular signal–regulated protein kinase activity. Endothelial cells underwent apoptosis when cultured in a serum-free medium, which was prevented by bFGF. D5 reversed the protective effect of bFGF by 80%. Cells treated with D5 in the presence of bFGF showed typical morphological features of apoptosis, which was further confirmed by 2 additional assays: Hoechst 33258 cell staining and DNA fragmentation analysis. We conclude that the inhibition of endothelial cell proliferation and induction of apoptosis together represent a major contribution to the antiangiogenic activity of D5.
Raman Spectroscopic Evaluation of the Effects of Diet and Lipid-Lowering Therapy on Atherosclerotic Plaque Development in Mice
Authors: van de Poll Sweder W.E. , Römer Tjeerd J. , Volger Oscar L. , Delsing Dianne J.M. , Bakker Schut Tom C. , Princen Hans M.G. , Havekes Louis M. , Jukema J. Wouter , van der Laarse Arnoud , Puppels Gerwin J.
Published: September 2007

Quantitative characterization of atherosclerotic plaque composition with standard histopathological methods remains limited to sectioned plaques. Raman spectroscopy enables nondestructive quantification of atherosclerotic plaque composition. We used Raman spectroscopy to study the effects of diet and lipid-lowering therapy on plaque development in apolipoprotein (APO) E*3-Leiden transgenic mice. Raman spectra were obtained over the full width and entire length of the ascending aorta and aortic arch. Spectra were modeled to calculate the relative dry weights of cholesterol and calcium salts, and quantitative maps of their distribution were created. In male mice (n=20) that received a high-fat/high-cholesterol (HFC) diet for 0, 2, 4, or 6 months, Raman spectroscopy showed good correlation between cholesterol accumulation and total serum cholesterol exposure (
r
≈0.87,
P
<0.001). In female mice (n=10) that were assigned to an HFC diet, with or without 0.01% atorvastatin, a strong reduction in cholesterol accumulation (57%) and calcium salts (97%) (
P
<0.01) was demonstrated in the atorvastatin-treated group. In conclusion, Raman spectroscopy can be used to quantitatively study the size and distribution of depositions of cholesterol and calcification in APOE*3-Leiden transgenic mice. This study encourages Raman spectroscopy for the quantitative investigation of atherosclerosis and lipid-lowering therapy in larger animals or humans in vivo.
Effect of γ-Irradiation and Bone Marrow Transplantation on Atherosclerosis in LDL Receptor-Deficient Mice
Authors: Schiller Natalie K. , Kubo Nobuhiko , Boisvert William A. , Curtiss Linda K.
Published: September 2007

Abstract—

Bone marrow transplantation (BMT) is commonly used to study the participation of bone marrow-derived cells in atherosclerosis. To determine the effect of this methodology on lesions, 16 male low density lipoprotein (LDL) receptor knockout (LDLr−/−) mice were reconstituted with bone marrow from syngeneic LDLr−/− mice after 10 Gy γ-irradiation and compared with 12 male LDLr−/− littermates that did not undergo BMT (no-BMT group). Mice were fed a high fat diet (HFD) for 16 weeks to induce atherosclerosis. Sixteen additional LDLr−/− mice underwent BMT, and 12 male LDLr−/− mice that did not undergo BMT were fed a chow diet for 56 weeks. Thoracic aorta lesion areas were smaller in BMT mice than in no-BMT mice fed the HFD (
P
<0.0001). In contrast, aortic root lesion areas were greater in the BMT mice fed the HFD (
P
<0.0001) as well as in those fed the chow diet (
P
=0.0001). Abdominal aorta free cholesterol and cholesteryl ester mass were minimal in all groups studied. Aortic root lesions from all no-BMT mice were densely collagenous and encapsulated by a cellular cap, whereas lesions in the BMT mice contained lipid cores and minimal collagen staining. Although the reason for these differences in lesion size and composition remains unresolved, this study suggests that multiple parameters of lesion formation should be examined to assess atherosclerosis.
Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator–Activated Receptor-α–Mediated Downregulation of Cholesterol 7α-Hydroxylase and Sterol 27-Hydroxylase Expression
Authors: Post Sabine M. , Duez Hélène , Gervois Philippe P. , Staels Bart , Kuipers Folkert , Princen Hans M.G.
Published: September 2007

Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator–activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased incidence of cholesterol gallstones. In this study, we investigated the effect of fibrates on bile acid synthesis. Ciprofibrate and the PPARα agonist Wy14,643 decreased bile acid synthesis in cultured rat hepatocytes and suppressed cholesterol 7α-hydroxylase and sterol 27-hydroxylase activities, paralleled by a similar reduction of the respective mRNAs. Treatment of rats with 0.05% (wt/wt) ciprofibrate decreased cholesterol 7α-hydroxylase enzyme activity and mRNA. The functional involvement of PPARα in the suppression of both enzymes was proven with the use of PPARα-null mice. In wild-type mice, ciprofibrate reduced cholesterol 7α-hydroxylase and sterol 27-hydroxylase enzyme activities and mRNA. The decrease in mRNA of both enzymes is regulated transcriptionally and posttranscriptionally, respectively, resulting in a decline in the output of fecal bile acids (−45%) and a 3-fold increase in fecal cholesterol secretion. These effects were completely abolished in PPARα-null mice. A decreased bile acid production by PPARα-mediated downregulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment.
Aortic Pulse Wave Velocity Predicts Cardiovascular Mortality in Subjects >70 Years of Age
Authors: Meaume S. , Benetos A. , Henry O.F. , Rudnichi A. , Safar M.E.
Published: September 2007

Aortic pulse wave velocity (PWV) is a significant and independent predictor of cardiovascular mortality in subjects with essential hypertension and in patients with end-stage renal disease. Its contribution to cardiovascular risk in subjects 70 to 100 years old has never been tested. A cohort of 141 subjects (mean±SD age, 87.1±6.6 years) was studied in 3 geriatrics departments in a Paris suburb. Together with sphygmomanometric blood pressure measurements, aortic PWV was measured with a validated automatic device. During the 30-month follow-up, 56 patients died (27 from cardiovascular events). Logistic regressions indicated that age (
P
=0.005) and a loss of autonomy (
P
=0.01) were the best predictors of overall mortality. For cardiovascular mortality, aortic PWV was the major risk predictor (
P
=0.016). The odds ratio was 1.19 (95% confidence interval, 1.03 to 1.37). Antihypertensive drug treatment and blood pressure, including systolic and pulse pressure, had no additive role. In subjects 70 to 100 years old, aortic PWV is a strong, independent predictor of cardiovascular death, whereas systolic or pulse pressure was not. This prospective result will need to be confirmed in an intervention trial.
Consumption of Whole Grain and Legume Powder Reduces Insulin Demand, Lipid Peroxidation, and Plasma Homocysteine Concentrations in Patients With Coronary Artery Disease
Authors: Jang Yangsoo , Lee Jong Ho , Kim Oh Yoen , Park Hyun Young , Lee Sang Yun
Published: September 2007

Our objective was to evaluate whether isocaloric replacement of refined rice with whole grains and other plant products as a form of powder reduces coronary artery disease (CAD) risk factors, such as insulin demand and lipid peroxidation in CAD patients. Seventy-six male patients with CAD were randomly assigned to either a group ingesting a whole-grain meal daily or a control group for 16 weeks. In the whole-grain group, serum concentrations of glucose and insulin decreased by 24% and 14%, respectively, without altering body weight and energy intake, whereas daily intakes of fiber and vitamin E increased by 25% and 41%, respectively. Consumption of whole grains and legume powder in CAD patients without diabetes decreased fasting levels of glucose and insulin. The areas under the curve for insulin and glucose during the oral glucose tolerance test were also decreased. CAD patients with diabetes in the whole-grain group also showed reductions in fasting glucose and in the area under the curve for glucose. In the whole-grain group, plasma malondialdehyde and homocysteine and urinary 8-epi-prostaglandin F
2α
concentrations decreased by ≈28%. Also, lipid-corrected concentrations of α-carotene, retinol, tocopherols, and lycopene increased by 11% to 40%, and the percentage composition of n-6 fatty acids of serum phospholipid increased by 14% in the whole-grain group. The replacement of refined rice with whole grain and legume powder as a source of carbohydrate in a meal showed significant beneficial effects on glucose, insulin, and homocysteine concentrations and lipid peroxidation in CAD patients. These effects are likely to substantially reduce the risk factors for CAD and diabetes.
Effect of Statin Therapy on Remnant Lipoprotein Cholesterol Levels in Patients With Combined Hyperlipidemia
Authors: Stein Daniel T. , Devaraj Sridevi , Balis David , Adams-Huet Beverley , Jialal Ishwarlal
Published: September 2007

Clinical trials with statins have demonstrated significant reductions in cardiovascular events. Remnant lipoproteins are independent predictors of cardiovascular events. Because of the paucity of data on the effect of statins on remnant lipoproteins, we tested the effect of pravastatin, simvastatin, and atorvastatin on remnant lipoprotein cholesterol (RLP-C) levels in a randomized crossover study in patients with combined hyperlipidemia. After a 6-week diet phase, patients (n=22) were randomized to pravastatin (40 mg/d), simvastatin (20 mg/d), or atorvastatin (10 mg/d) for 6 weeks, with a 3-week washout between each drug. All 3 drugs significantly decreased total and low density lipoprotein (LDL) cholesterol (
P
<0.001). Mean reduction in LDL cholesterol with pravastatin, simvastatin, and atorvastatin was 21%, 29%, and 32%, respectively. None of the drugs affected high density lipoprotein cholesterol levels. Median levels of triglycerides were significantly reduced with simvastatin (26%,
P
=0.001) and atorvastatin (24%,
P
=0.0001) but not with pravastatin (9%,
P
=0.18). Non–high density lipoprotein cholesterol decreased significantly with all 3 statins (20%, 29%, and 32% with pravastatin, simvastatin, and atorvastatin, respectively;
P
<0.001). Median RLP-C levels were significantly reduced with simvastatin (6%,
P
<0.05) and atorvastatin (25.9%,
P
<0.001) but not with pravastatin (2.9%,
P
=0.58). Thus, atorvastatin and simvastatin, in addition to reducing LDL cholesterol and triglyceride levels, significantly reduced RLP-C levels. This could be another potential mechanism to explain their cardiovascular benefits.
Predictors of Uncontrolled Hypertension in Ambulatory Patients
Authors: Knight Eric L. , Bohn Rhonda L. , Wang Philip S. , Glynn Robert J. , Mogun Helen , Avorn Jerry
Published: September 2007

Hypertension remains poorly controlled in the United States. Improvement of its management will require an understanding of the patient characteristics and treatment factors associated with uncontrolled hypertension. We studied antihypertensive medication use, comorbidity, and blood pressure measurements for 525 hypertensive patients in 3 different healthcare systems over a 1-year period. We concomitantly conducted comprehensive patient interviews covering demographic factors, knowledge of hypertension and its treatment, and medication side effects. Ordinal logistic regression was used to identify factors associated with poor blood pressure control. Mean age of the patients was 65±11 years. Mean systolic blood pressure (SBP) was 143±15 mm Hg; and mean diastolic blood pressure (DBP), 80±9 mm Hg. Only 39% (203/525) of patients had mean blood pressure <140/90 mm Hg during the study period; about half (257/525) had stage 1 hypertension (mean SBP 140 to 159 mm Hg and/or mean DBP 90 to 99 mm Hg), and 12% (65/525) had stage 2 or greater hypertension (SBP >160 mm Hgand/or DBP >100 mm Hg). Multivariate analysis revealed several independent predictors of poor control: older age, multi-drug regimens, lack of knowledge by the patient of their target SBP, and a report of antihypertensive drug side effects. Patients with angina had a higher likelihood of adequate blood pressure control. Fewer than 40% of the treated patients studied had a mean blood pressure ≤140/90 mm Hg, and specific patient-related factors appear to predict poor control. Some of these may be amenable to modification. Further identification of patients at risk of poor control can lead to targeted interventions to improve management.
Antihypertensive Action of Amiodarone in Spontaneously Hypertensive Rats
Authors: Dias da Silva Valdo José , Cavalcante Viana Publio Cesar , de Melo Alves Rodrigo , Salgado Helio Cesar , Montano Nicola , Fazan Rubens
Published: September 2007

Abstract—— The antihypertensive effect of amiodarone was investigated in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The SHR and WKY were treated with amiodarone (1 mg/mL PO) or tap water (control) for 20 weeks. The indirect arterial pressure (AP) was monitored weekly using the tail-cuff method. At the end of the 20th week, the direct AP was measured, and the systolic AP and pulse interval time series were submitted to autoregressive spectral analysis. In addition, cardiac baroreflex sensitivity and left ventricular weight were evaluated as well. The indirect AP was reduced 1 week after the beginning of amiodarone treatment. The direct mean AP and pulse interval were, respectively, 135±8 mm Hg and 191±3 ms in SHR treated with amiodarone (187±8 mm Hg and 156±7 ms in control SHR,P<0.05) and 87±3 mm Hg and 207±8 ms in WKY treated with amiodarone (105±8 mm Hg and 174±4 ms in control WKY,P<0.05). In SHR treated with amiodarone, the low-frequency oscillations of AP were lower (8.5±1.2 mm Hg2versus 14.4±2.9 mm Hg2in control SHR,P<0.05), whereas the reflex bradycardia was higher (0.84±0.12 ms/mm Hg versus 0.32±0.22 ms/mm Hg in control SHR,P<0.05). The left ventricle weight was also smaller in SHR treated with amiodarone (2.94±0.12 mg/g versus 3.45±0.24 mg/g in control SHR,P<0.05). In WKY, amiodarone induced similar changes as in SHR, except for a lack of effect in the left ventricle weight. These data indicate that amiodarone has an antihypertensive action in SHR that is associated with a reduction in vasomotor sympathetic modulation, an increase in vagal cardiac baroreflex sensitivity, and a decrease in cardiac hypertrophy.
Vascular Remodeling in Hypertension
Authors: Intengan Hope D. , Schiffrin Ernesto L.
Published: September 2007

Abstract
—

— Remodeling of large and small arteries contributes to the development and complications of hypertension. The focus of this review is some of the mechanisms involved in the remodeling of small arteries in hypertension. In hypertension, changes in small artery structure are basically of 2 kinds: (1) inward eutrophic remodeling, in which outer and lumen diameters are decreased, media/lumen ratio is increased, and cross-sectional area of the media is unaltered; and (2) hypertrophic remodeling, in which the media thickens to encroach on the lumen, resulting in increased media cross-sectional area and media/lumen ratio. Growth, apoptosis, inflammation, and fibrosis contribute to vascular remodeling in hypertension. Apoptosis is gene-regulated cell death, with minimal membrane disruption and inflammation, that counters cell proliferation and fine-tunes developmental growth. Apoptosis has been reported in hypertension to be both increased and decreased in different tissues, including blood vessels. Inflammation, which may be low grade, probably plays an important role in triggering fibrosis in cardiovascular disease and hypertension. Vascular fibrosis entails accumulation of collagen, fibronectin, and other extracellular matrix components in the vessel wall and is an important aspect of extracellular matrix remodeling in hypertension. Associated with this, there may be increases in cell-matrix attachment sites (integrins) and changes in their topographical localization that may modulate arterial structure. Imbalance in matrix metalloproteinase/tissue inhibitors of metalloproteinases may contribute to alteration in collagen turnover and extracellular matrix remodeling. Chronic vasoconstriction may lead to embedding of the contracted vessel structure in a remodeled extracellular matrix, contributing to the inward remodeling of the blood vessel as smooth muscle cells are rearranged around a smaller lumen. The resulting remodeling of small arteries may initially be adaptive, but eventually it becomes maladaptive and compromises organ function, contributing to cardiovascular complications of hypertension.
Carotid Pressure Is a Better Predictor of Coronary Artery Disease Severity Than Brachial Pressure
Authors: Waddell Tamara K. , Dart Anthony M. , Medley Tanya L. , Cameron James D. , Kingwell Bronwyn A.
Published: September 2007

The mechanisms relating pulse pressure to cardiovascular outcome may include surrogacy for coronary disease severity. Although pulse pressure is typically measured at the brachial artery, central pulse pressure and its principal determinant, large-artery stiffness, may relate more closely to disease severity. This study aimed to determine the relationships between large-artery stiffness and carotid and brachial blood pressures and coronary artery disease severity. One hundred fourteen male patients with coronary artery disease (age 60±8 years, mean±SD) and 57 age-matched healthy male controls (age 59±9 years) were recruited. Patients were classified into 2 groups based on the magnitude of their maximum coronary stenosis: moderate (50% to 89%) and severe (≥90%). Large-artery stiffness was assessed as systemic arterial compliance and carotid-femoral pulse wave velocity. Mean pressure was not different between the 3 groups. Systemic compliance and carotid pulse pressure were significantly different between all 3 groups, with compliance lowest and pressure highest in the severe group (
P
<0.05). Pulse wave velocity was higher in patients with severe stenosis than in those with moderate stenosis (
P
<0.01) and those in the control group (
P
<0.001). Brachial pulse pressure was higher in patients than in controls (
P
<0.05), but there was no difference between the 2 disease groups. In separate multivariate analyses, carotid pressures and systemic arterial compliance were determinants of coronary artery disease severity, independent of age, smoking status, body mass index, mean arterial pressure, heart rate, cholesterol levels (total, LDL, and HDL), triglycerides, and β-antagonist and lipid-lowering therapy (
P
<0.001), whereas brachial pressures and pulse wave velocity were not. In conclusion, central blood pressures and systemic arterial compliance are more sensitive markers of coronary artery disease severity than brachial pressures.
Arterial Calcifications, Arterial Stiffness, and Cardiovascular Risk in End-Stage Renal Disease
Authors: Blacher Jacques , Guerin Alain P. , Pannier Bruno , Marchais Sylvain J. , London Gérard M.
Published: September 2007

To test the predictive values of and independent contributions to cardiovascular and all-cause mortality of various arterial parameters exploring characteristics of the arterial wall at different sites, we studied prospectively 110 stable end-stage renal disease patients on hemodialysis. These parameters involved carotid diameter, carotid intima-media thickness, carotid compliance, carotid distensibility, carotid incremental elastic modulus, aortic diameter, aortic pulse wave velocity, and the presence of arterial calcifications measured at the sites of the carotid artery, abdominal aorta, iliofemoral axis, and legs. The presence of calcifications was analyzed semiquantitatively as a score (0 to 4) according to the number of arterial sites with calcifications. During a follow-up of 53±21 months (mean±SD), 25 cardiovascular and 14 noncardiovascular deaths occurred. In univariate analysis, the carotid incremental elastic modulus was the most closely related to prognosis. Risk of death increased with the number of vascular sites involved by calcifications. Moreover, information (in terms of prediction) given by carotid elastic incremental modulus was additive to the presence and extent of vascular calcification-related prediction value. Adjusted hazard ratios of all-cause and cardiovascular mortality for an increase of 1 unit in calcification score were 1.9 (95% confidence interval [CI], 1.4 to 2.6) and 2.6 (95% CI, 1.5 to 4.4), respectively (
P
<0.001 for both). Adjusted hazard ratios of all-cause and cardiovascular mortality for a 1-SD increase in carotid incremental elastic modulus were 1.6 (95% CI, 1.2 to 2.2) and 1.7 (95% CI, 1.2 to 2.4), respectively (
P
<0.01 for both). The results of this study showed that the presence and extent of vascular calcifications were strong predictors of cardiovascular and all-cause mortality. Carotid incremental elastic modulus gave additional predictive value.
Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism
Authors: Mazzali Marilda , Hughes Jeremy , Kim Yoon-Goo , Jefferson J. Ashley , Kang Duk-Hee , Gordon Katherine L. , Lan Hui Y. , Kivlighn Salah , Johnson Richard J.
Published: September 2007

An elevation in circulating serum uric acid is strongly associated with the development of hypertension and renal disease, but whether uric acid has a causal role or whether it simply indicates patients at risk for these complications remains controversial. We tested the hypothesis that uric acid may have a causal role in the development of hypertension and renal disease by examining the effects of mild hyperuricemia in rats. Mild hyperuricemia was induced in rats by providing a uricase inhibitor (oxonic acid) in the diet. Hyperuricemic rats developed elevated blood pressure after 3 weeks, whereas control rats remained normotensive. The development of hypertension was prevented by concurrent treatment with either a xanthine oxidase inhibitor (allopurinol) or a uricosuric agent (benziodarone), both of which lowered uric acid levels. Blood pressure could also be lowered by reducing uric acid levels with either allopurinol or oxonic acid withdrawal. A direct relationship was found between blood pressure and uric acid (
r
=0.75, n=69), with a 10–mm Hg blood pressure increase for each 0.03-mmol/L (0.5-mg/dL) incremental rise in serum uric acid. The kidneys were devoid of urate crystals and were normal by light microscopy. However, immunohistochemical stains documented an ischemic type of injury with collagen deposition, macrophage infiltration, and an increase in tubular expression of osteopontin. Hyperuricemic rats also exhibited an increase in juxtaglomerular renin and a decrease in macula densa neuronal NO synthase. Both the renal injury and hypertension were reduced by treatment with enalapril or
l
-arginine. In conclusion, mild hyperuricemia causes hypertension and renal injury in the rat via a crystal-independent mechanism, with stimulation of the renin-angiotensin system and inhibition of neuronal NO synthase.
Effects of Antisense Oligodeoxynucleotide Targeting of the α2B-Adrenergic Receptor Messenger RNA in the Central Nervous System
Authors: Kintsurashvili Ekaterina , Gavras Irene , Johns Conrado , Gavras Haralambos
Published: September 2007

The results of previous studies with genetically engineered mice have suggested that an intact central α2B-adrenergic receptor (α2B-AR) subtype mediates the development and maintenance of salt-induced hypertension. In the present study, we sought to further define the role of this receptor by injecting antisense oligodeoxynucleotides (AS-ODNs), targeting a selected sequence of the α2B-AR mRNA, into the lateral cerebral ventricle of rats that had undergone prior subtotal nephrectomy and dietary salt loading. Cell culture studies showed that these AS-ODNs could block α2B-AR protein generation. Before AS-ODN injection, blood pressure (BP) averaged 133±5 mm Hg during the daytime and rose to 165±4 mm Hg during the nighttime activity hours (P<0.001 versus baseline average of 120±2 mm Hg). The injection of AS-ODNs during the early afternoon prevented the BP rise and was associated with a significant fall in heart rate (from 385±12 to 306±15 bpm,P<0.05) and symptoms of sedation that lasted for several hours, with a peak at 3 to 6 hours and full recovery by 24 hours. At that time, a second injection produced identical effects in all rats (n=9). Control rats (n=10) that received scrambled ODN injections had no changes in BP or heart rate patterns, and neither group had evidence of neurotoxicity, indicating that these effects are specifically due to translational inhibition of central α2B-AR. We conclude that a fully functional central α2B-AR is necessary for the induction of salt-dependent hypertension.
Gender Differences in Associations of Diurnal Blood Pressure Variation, Awake Physical Activity, and Sleep Quality With Negative Affect
Authors: Kario Kazuomi , Schwartz Joseph E. , Davidson Karina W. , Pickering Thomas G.
Published: September 2007

This study reports on the associations among depression, anxiety, awake physical activity, sleep quality (assessed by nocturnal physical activity), and diurnal blood pressure (BP) variation in a nonpsychiatric sample (The Work Site Blood Pressure Study). We conducted ambulatory BP (ABP) monitoring and actigraphy in 231 working men and women. Depression and anxiety were measured by the Brief Symptom Inventory. There were gender-specific associations between depression or anxiety and ABP parameters. In men, depression was associated positively with the sleep/awake systolic BP (SBP) ratio (
r
=0.24,
P
=0.006). After controlling for age, body mass index, and awake and sleep activity, depression remained significantly associated with the sleep/awake SBP ratio (
r
=0.25,
P
=0.005) and was also significantly related to sleep SBP (
r
=0.21,
P
=0.02). Anxiety, which was related to depression (
r
=0.73,
P
<0.0001), had a similar but slightly weaker pattern of associations with ABP and activity. These associations were not found in women, but there were associations of anxiety with awake SBP (
r
=0.24,
P
=0.01) and pulse rate (
r
=0.27,
P
=0.006). In conclusion, depression is associated with disrupted diurnal BP variation independent of ambulatory physical activity in working men, whereas anxiety is associated with awake SBP and pulse rate in women.
Aging, Carotid Artery Distensibility, and the Ser422Gly Elastin Gene Polymorphism in Humans
Authors: Hanon Olivier , Luong Vu , Mourad Jean Jacques , Bortolotto Luiz A. , Jeunemaitre Xavier , Girerd Xavier
Published: September 2007

Elastin is a protein of the extracellular matrix that forms the major component of elastic fibers from the arterial wall thickness and plays an important role in elastic properties of large blood vessels. To study the relationships between the Ser422Gly polymorphism in exon 16 of the gene-encoding elastin and the distensibility of 2 different arteries, the radial artery (a muscular artery) and the common carotid artery (an elastic artery), we studied a cohort of 320 subjects (49±12 years of age) without evidence of cardiovascular disease and who had never been treated with cardiovascular drugs. Distensibility and elastic modulus were evaluated for the common carotid and the radial arteries with high-resolution echo-tracking devices (NIUS-02 and Wall Track System). The A-to-G nucleotide change corresponding to the Ser422Gly amino acid change was studied by digestion of polymerase chain reaction products with
Bst
NI.

Results indicate that genotype frequencies (AA=10%, AG=51%, GG=39%) were in agreement with the Hardy-Weinberg equilibrium. For the carotid artery, a significant decrease in distensibility was observed in subjects carrying the A allele (with AA+AG genotypes) compared with subjects with the GG genotype (13.8±6.4 kPa
−1
· 10
−3
versus 15.9±6.2 kPa
−1
· 10
−3
,
P
<0.01), assuming a dominant effect of the A allele. Moreover, the presence of the A allele was associated with a significant increase in elastic modulus (0.98±0.40 kPa · 10
3
in subjects with AA+AG genotypes versus 0.83±0.41 kPa · 10
3
in subjects with GG genotypes,
P
<0.01). Multivariate analysis indicated that these results were observed after adjustment for age, gender, and mean arterial blood pressure (
P
<0.01). In contrast, no association was found between arterial parameters and genotypes for the radial artery. The 2-way analysis of covariance adjusted for mean arterial blood pressure indicated that the association between the A allele and distensibility of the carotid artery was observed only in subjects >50 years of age, assuming for carotid distensibility a significant age effect (
P
<0.01), genotype effect (
P
=0.01), and age-genotype interaction (
P
=0.04). The present results indicate a relationship between the Ser422Gly polymorphism and the distensibility of elastic arteries but not of muscular arteries and suggest that there is an age-genotype interaction for carotid artery distensibility.
Biochemical Assessment of Myocardial Fibrosis in Hypertensive Heart Disease
Authors: López Begoña , González Arantxa , Varo Nerea , Laviades Concepción , Querejeta Ramón , Díez Javier
Published: September 2007

Fibrous tissue accumulation is an integral feature of the adverse structural remodeling of cardiac tissue seen with hypertensive heart disease. Given the importance of fibrous tissue in leading to myocardial dysfunction and failure, noninvasive monitoring of myocardial fibrosis by use of serological markers of collagen turnover could prove a clinically useful tool, particularly given the potential for cardioprotective and cardioreparative pharmacological strategies. An emerging experimental and clinical experience holds promise for the use of radioimmunoassays of various serological markers of fibrillar collagen type I and type III turnover in arterial hypertension. More specifically, the measurement of serum concentrations of procollagen type I C-terminal propeptide (a peptide that is cleaved from procollagen type I during the synthesis of fibril-forming collagen type I) may provide indirect diagnostic information on both the extent of myocardial fibrosis and the ability of antihypertensive treatment to diminish collagen type I synthesis and reduce myocardial fibrosis. This approach represents an exciting and innovative strategy, and available data set the stage for larger trials, in which noninvasive measures of fibrosis in hypertensive heart disease could prove useful.
Gene Therapy for Cardiovascular Disease
Authors: Khurana Rohit , Martin John F. , Zachary Ian
Published: September 2007

There is currently intense interest in the development of gene therapy for cardiovascular disease. The stimulation of therapeutic angiogenesis for ischemic heart disease has been one of the areas of greatest promise. Encouraging results have been obtained with the angiogenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor in animal models, leading to clinical trials in ischemic heart disease. VEGF also has therapeutic potential in a second area of cardiovascular gene therapy, the enhancement of arterioprotective endothelial functions to prevent postangioplasty restenosis and bypass graft arteriopathy. The endothelial cell growth and survival functions of VEGF promote endothelial regeneration, whereas VEGF-induced endothelial production of NO and prostacyclin inhibits vascular smooth muscle cell proliferation. Inhibition of neointimal hyperplasia may also be achieved by gene transfer of endothelial NO synthase (eNOS), PGI synthase, or cell cycle regulators (retinoblastoma, cyclin or cyclin-dependent kinase inhibitors, p53, growth arrest homeobox gene,fasligand) or antisense oligonucleotides toc-myb,c-myc, proliferating cell nuclear antigen, and transcription factors such as nuclear factor κB and E2F. An improved understanding of etiologically complex pathologies involving the interplay of genes and the environment, such as atherosclerosis and systemic hypertension, has led to the identification of new targets for gene therapy, with the potential to alleviate inherited genetic defects such as familial hypercholesterolemia. The use of vasodilator gene overexpression and antisense knockdown of vasoconstrictors to reduce blood pressure in animal models of systemic and pulmonary hypertension offers the prospect of gene therapy for human hypertensive disease. The renin-angiotensin system has been the target of choice for antihypertensive strategies because of its wide distribution and additional effects on fibrinolytic and oxidative stress pathways. Gene therapy in cardiovascular disease has an exciting future but remains at an early stage. Further developments in gene transfer vector technology and the identification of additional target genes will be required before its full therapeutic potential can be realized.
Treatment of Congestive Heart Failure
Authors: Zannad Faiez , Dousset Brigitte , Alla François
Published: September 2007

Cardiac extracellular matrix undergoes extensive and continuous turnover involved in the lesion-reparation process, such as in cardiac remodeling, in hypertensive cardiac hypertrophy, in dilated cardiomyopathy, after myocardial infarction in the transition to heart failure, and during the progression of left ventricular dysfunction. Cardiac fibrosis is a major determinant of diastolic dysfunction and pumping capacity, and it may provide the structural substrate for arrhythmogenicity, thus potentially contributing the to progression of heart failure and sudden death. Aldosterone was shown to promote cardiac fibrosis in various experimental models. It was demonstrated that spironolactone may oppose the effect of aldosterone in promoting cardiac fibrosis. Measurement of cardiac collagen turnover by use of serological markers is a useful tool for monitoring cardiac tissue repair and fibrosis in experimental models or clinical conditions. We found that high serum levels of a marker of collagen turnover (procollagen type III N-terminal peptide ) in patients with chronic heart failure receiving conventional therapy, including ACE inhibitors, was associated with high mortality and hospitalization rates. In RALES (Randomized Aldactone Evaluation Study), in patients randomized to placebo, markers continued to increase or remained unchanged after 6-month follow-up. On the contrary, adding spironolactone 25 mg daily significantly decreased the levels of these serum markers during the same period. Most importantly, the spironolactone-related morbidity and mortality benefit was most predominant in subgroups with highest baseline levels of serum markers. These results suggest that limitation of the aldosterone-related excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with chronic heart failure.
Comparative Effects of Ramipril on Ambulatory and Office Blood Pressures
Authors: Svensson Per , de Faire Ulf , Sleight Peter , Yusuf Salim , Östergren Jan
Published: September 2007

In the HOPE-trial, the ACE inhibitor ramipril significantly reduced cardiovascular morbidity and mortality in patients at high risk for cardiovascular events. The benefit could only partly be attributed to the modest mean reduction of office blood pressure (OBP) during the study period (3/2 mm Hg). However, because according to the HOPE protocol ramipril was given once daily at bedtime and blood pressure was measured during the day, the 24-hour reduction of blood pressure may be underestimated based on OBP. Thirty-eight patients with peripheral arterial disease enrolled in the HOPE study underwent 24-hour ambulatory blood pressure (ABP) measurement before randomization and after 1 year. OBP was measured in the sitting position immediately before fitting the ABP measuring equipment to the patients. Ramipril did not significantly reduce OBP (8/2 mm Hg,
P
=NS) or day ABP (6/2 mm Hg,
P
=NS) after 1 year. Twenty-four–hour ABP was significantly reduced (10/4 mm Hg,
P
=0.03), mainly because of a more pronounced blood pressure lowering effect during nighttime (17/8 mm Hg,
P
<0.001). The night/day ratio was also significantly lowered in the ramipril group. ABP shows greater falls, especially at night, than OBP during treatment with ramipril given once daily at bedtime. Although, OBP is the correct comparator when comparing with previous large intervention trials and epidemiological studies, the effects on cardiovascular morbidity and mortality seen with ramipril in the HOPE study may, to a larger extent than previously ascribed, relate to effects on blood pressure patterns over the 24-hour period.
Apoptosis and Glomerular Injury After Prolonged Nitric Oxide Synthase Inhibition in Spontaneously Hypertensive Rats
Authors: Ono Hidehiko , Ono Yuko , Takanohashi Atsuko , Matsuoka Hiroaki , Frohlich Edward D.
Published: September 2007

This study was designed to investigate the relationship between apoptosis and glomerular injury in spontaneously hypertensive rats (SHR) with hypertensive disease that was exacerbated by inhibition of NO synthesis. Development of glomerular cell apoptosis was evaluated by assessment of renal hemodynamics, glomerular morphometric changes, and participation of the renin-angiotensin system. Three groups of 20-week-old SHR were investigated: control male SHR and 2 similar groups given 2 doses of
N
G
-nitro-
l
-arginine methyl ester (L-NAME, 50 or 80 mg/L, respectively) for 3 weeks. Mean arterial pressure and renal vascular resistance increased, whereas effective renal plasma flow and glomerular filtration rate were diminished by L-NAME. The small artery wall/lumen ratio increased as the glomerular-tuft area diminished. Renal cortical tissue levels of angiotensin II increased in response to the L-NAME, thereby inducing afferent arteriolar injury. Apoptosis and proliferative index (PCNA) of nonsclerotic glomeruli were induced by the low-dose L-NAME as the glomerular cell number decreased. In contrast, the PCNA index was downregulated with the high-dose L-NAME. These results indicate that angiotensin II activation, induced by L-NAME, was related to glomerular cell deletion and apoptosis together with the pathophysiological changes of severe nephrosclerosis and impaired renal dynamics.
Isolated Systolic Hypertension in Elderly WKY Is Reversed With
l
-Arginine and ACE Inhibition
Authors: Susic Dinko , Varagic Jasmina , Frohlich Edward D.
Published: September 2007

This study was designed to examine the preventability of progressive deterioration of cardiovascular structure and function in very old Wistar-Kyoto (WKY) rats with isolated systolic hypertension (ISH). To this end, male 18-month-old normotensive WKY rats were given either placebo or
l
-arginine (70 mg · kg
−1
· d
−1
) and an ACE inhibitor (enalapril, 30 mg · kg
−1
· d
−1
) for 6 months. These control and treated rats were studied at the age of 2 years by examining: cardiovascular mass and collagen content, cardiac function, and systemic and regional (including coronary) hemodynamics. Additional data obtained in adult, 35-week-old WKY are included for comparison. ISH associated with increased total peripheral resistance was found in the old, untreated WKY, and this was prevented by the combined treatment. The untreated rats also exhibited impaired left ventricular function, as denoted by increased left ventricular end-diastolic pressure and reduced maximal rates of rise and fall of left ventricular pressure. These functional changes were also ameliorated with the combined treatment. Coronary hemodynamics were also compromised in the untreated WKY; and therapy improved coronary flow reserve and minimal coronary vascular resistance in both ventricles of the old WKY in parallel with reduction of arterial pressure. Blood flow to various other organs was uncompromised in the old rats, although increased vascular resistances were observed in untreated old WKY with ISH. These changes were also improved by the combined therapy. Finally, therapy diminished left ventricular mass and collagen concentration in old WKY compared with the untreated WKY. However, when compared with the 35-week-old WKY, both groups of old WKY (untreated and treated) demonstrated myocardial fibrosis, depressed ventricular function, and compromised coronary hemodynamics. Therefore,
l
-arginine and ACE inhibitory therapy ameliorated the hypertensive and associated adverse cardiovascular changes in old WKY, although it failed to improve totally the progressive deterioration of cardiovascular structure and function that occurred with aging. The results suggest that different mechanisms may be responsible for the hypertension- and age-related cardiovascular changes, although they may appear to be similar.
Oxidative Stress in Arterial Hypertension
Authors: Zalba Guillermo , José Gorka San , Moreno María U. , Fortuño María A. , Fortuño Ana , Beaumont Francisco J. , Díez Javier
Published: September 2007

Increased vascular reactive oxygen species production, especially superoxide anion, contributes significantly in the functional and structural alterations present in hypertension. An enhanced superoxide production causes a diminished NO bioavailability by an oxidative reaction that inactivates NO. Exaggerated superoxide levels and a low NO bioavailability lead to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that the enzyme NAD(P)H oxidase plays a major role as the most important source of superoxide anion in vascular cells. Several experimental observations have shown an enhanced superoxide generation as a result of the activation of vascular NAD(P)H oxidase in hypertension. Although this enzyme responds to stimuli such as vasoactive factors, growth factors, and cytokines, some recent data suggest the existence of a genetic background modulating the expression of its different components. New polymorphisms have been identified in the promoter of the p22
phox
gene, an essential subunit of NAD(P)H oxidase, influencing the activity of this enzyme. Genetic investigations of these polymorphisms will provide novel markers for determination of genetic susceptibility to oxidative stress in hypertension.
History About the Discovery of the Renin-Angiotensin System
Authors: Basso Nidia , Terragno Norberto A.
Published: September 2007

The history of the discovery of the renin-angiotensin system began in 1898 with the studies made by Tigerstedt and Bergman, who reported the pressor effect of renal extracts; they named the renal substance renin based on its origin. In 1934, Harry Goldblatt induced experimental hypertension in dogs by clamping a renal artery. About 1936, simultaneously in the Medical School of the University of Buenos Aires, Argentina, and in the Eli-Lilly Laboratories in Indianapolis, 2 independent groups of researchers, using the Goldblatt technique to produce experimental hypertension, demonstrated renal secretion of a pressor agent similar to renin. In the following years, both teams described the presence of a new compound in the renal vein blood of ischemic kidneys. This agent was extracted from blood with 70% acetone and had a short pressor effect. The final conclusion was that renin acted enzymatically on a plasma protein to produce the new substance. In Buenos Aires, it was called hypertensin; in the United States, angiotonin. In 1958, Eduardo Braun Menéndez from Argentina and Irving H. Page from the United States agreed to name it angiotensin.
Lesion Volume Change After Treatment With Tissue Plasminogen Activator Can Discriminate Clinical Responders From Nonresponders
Authors: Merino José G. , Latour Lawrence L. , Todd Jason W. , Luby Marie , Schellinger Peter D. , Kang Dong-Wha , Warach Steven
Published: September 2007

Background and Purpose—

A change in acute-to-chronic lesion volume has been proposed as a biomarker for stroke therapies. The objectives of this study were to determine the magnitude of lesion volume change after standard treatment with tissue plasminogen activator and to determine whether specific volume change thresholds can discriminate clinical responders from nonresponders.

Methods—

We measured lesion volume on diffusion weighted at baseline and on 90-day fluid attenuated inversion recovery MRI and scored 3-month modified Rankin Scale in consecutive patients treated with tissue plasminogen activator. We identified variables associated with excellent (modified Rankin Scale 0 to 1) and independent (modified Rankin Scale 0 to 2) outcomes.

Results—

We included 53 patients (mean age 69 years, median baseline National Institutes of Health Stroke Scale score 7). The mean acute-to-chronic lesion volume increase was 11.7 (±7.7) cm
3
. In 23 patients, the chronic lesion was smaller than the baseline lesion. At 3 months, 32 patients had an excellent clinical outcome. Dichotomous volume change variables associated with outcome included decrease in volume ≥30% (
P
=0.004) and volume increase ≥5 cm
3
(
P
=0.002).

Conclusions—

In patients given standard tissue plasminogen activator therapy, changes in lesion volume are associated with clinical outcome, and threshold lesion volumes can differentiate excellent and poor outcome, suggesting these as a potential marker of outcome.