bluuebunny/crossref_metadata_2025 huggingface dataset:
S17834, a New Inhibitor of Cell Adhesion and Atherosclerosis That Targets NADPH Oxidase
Authors: Cayatte Antonio J. , Rupin Alain , Oliver-Krasinski Jennifer , Maitland Karlene , Sansilvestri-Morel Patricia , Boussard Marie-France , Wierzbicki Michel , Verbeuren Tony J. , Cohen Richard A.
Published: September 2007

Oxidant stress is involved in the events that accompany endothelial cell expression of adhesion molecules and leukocyte adherence in many disease states, including atherosclerosis. A recently discovered benzo(b)pyran-4-one derivative, S17834 (10 to 50 μmol/L), reduced tumor necrosis factor-stimulated vascular cell adhesion molecule-1 (VCAM) mRNA accumulation and protein expression in human umbilical vein endothelial cells. Intercellular cell adhesion molecule-1 and E-selectin were also inhibited by S17834, but platelet endothelial cell adhesion molecule-1 was not. Adherence of U937 monocytic cells to the endothelial cells as well as to plastic plates coated with soluble VCAM, intercellular cell adhesion molecule-1, P-selectin, and E-selectin was also decreased. Consistent with an antioxidant mechanism of action, S17834 (10 to 50 μmol/L) inhibited tumor necrosis factor-stimulated release of superoxide from endothelial cells measured by cytochrome
c
reduction. S17834 had no effect on superoxide produced by xanthine oxidase, indicating that rather than by acting as a scavenger of superoxide anion, the drug acts by inhibiting the production of free radicals. Indeed, S17834 inhibited NADPH oxidase activity of endothelial cell membranes. The ability to inhibit superoxide anion production appears to be key in the effect of S17834 on superoxide anion production and VCAM expression, because these actions were mimicked by adenovirus-mediated overexpression of superoxide dismutase. Furthermore, these actions may be relevant in vivo, because S17834 reduced aortic superoxide anion levels by 40% and aortic atherosclerotic lesions by 60% in apolipoprotein E-deficient mice. These results indicate that S17834 inhibits adhesion molecule expression and adherence of leukocytes to endothelial cells as well as aortic atherogenesis and that perhaps these effects can be explained by its ability to inhibit endogenous superoxide anion production.
Cholesterol Absorption, Synthesis, and Fecal Output in Postmenopausal Women With and Without Coronary Artery Disease
Authors: Rajaratnam Radhakrishnan A. , Gylling Helena , Miettinen Tatu A.
Published: September 2007

Abstract
—

Hypercholesterolemia is a prominent risk factor for coronary artery disease (CAD), yet cholesterol metabolism has not been evaluated in women with CAD. The objective of this study was to determine the interrelations of CAD, serum squalene and sterols, and cholesterol metabolism with each other in postmenopausal women. For this purpose, we measured serum squalene and sterols and fecal steroids (cholesterol and bile acids) and squalene by gas-liquid chromatography and evaluated cholesterol absorption and synthesis in postmenopausal women with CAD (n=29) and age-matched controls (n=20). On similar dietary lipid intake, the cholesterol absorption efficiency and mean serum cholesterol level were comparable, but the squalene-to-cholesterol ratio was higher in cases than in controls. The presence of CAD was inversely associated with fecal total steroids (logistic regression coefficient β/SE=−2.11,
P
=0.04) and cholesterol synthesis (β/SE=−2.14,
P
=0.04) and turnover (β/SE=−2.19,
P
=0.03) after adjustment for dietary cholesterol, family history of CAD, smoking, low and high density lipoprotein cholesterol, and serum triglyceride levels. A high serum squalene ratio was not related to cholesterol synthesis but was inversely related to fecal squalene excretion, which was lower in cases than in controls. In conclusion, the presence of CAD in postmenopausal women is independently associated with altered cholesterol metabolism, as reflected by low synthesis and inefficient elimination of cholesterol.
Association Between P-Selectin Gene Polymorphisms and Soluble P-Selectin Levels and Their Relation to Coronary Artery Disease
Authors: Barbaux Sandrine C. , Blankenberg Stefan , Rupprecht Hans J. , Francomme Carole , Bickel Christoph , Hafner Gerd , Nicaud Viviane , Meyer Jürgen , Cambien François , Tiret Laurence
Published: September 2007

Abstract—

P-selectin is a cellular adhesion molecule that mediates the interaction of activated endothelial cells or platelets with leukocytes. Increased levels of soluble P-selectin have been reported in various cardiovascular disorders. We measured serum soluble P-selectin levels as well as 3 polymorphisms of the P-selectin gene (C-2123G, A-1969G, and Thr715Pro) in a large cohort of patients with documented coronary artery disease (n=869) and a healthy control group (n=334). The 3 P-selectin polymorphisms were strongly associated with P-selectin levels and altogether explained 7.3% and 18.6% of the P-selectin variability in patients and controls, respectively. Genotype distributions did not significantly differ between patients and controls. P-selectin levels were increased in patients younger than 55 years of age compared with controls (135.2 vs 114.3 ng/mL,
P
<0.01). On the contrary, patients older than 65 years of age had significantly lower P-selectin levels than did controls (121.5 vs 134.7 ng/mL,
P
<0.02). In intermediate age groups, P-selectin levels did not significantly differ between the 2 groups. In conclusion, this study revealed a strong association between P-selectin gene polymorphisms and serum P-selectin levels and a complex age-dependent relation between soluble P-selectin levels and coronary artery disease, which suggests that this molecule might have different roles in the atherothrombotic process.
Induction of Endothelial NO Synthase by Hydrogen Peroxide via a Ca
2+
/Calmodulin-Dependent Protein Kinase II/Janus Kinase 2–Dependent Pathway
Authors: Cai Hua , Davis Michael E. , Drummond Grant R. , Harrison David G.
Published: September 2007

We have recently demonstrated that hydrogen peroxide (H
2
O
2
) is an extremely potent stimulus of endothelial NO synthase (eNOS) gene expression. The present study was designed to identify the signaling mechanisms mediating this response. Induction of eNOS expression by H
2
O
2
was found to be Ca
2+
dependent, inasmuch as it was blocked by BAPTA-AM. Further studies have indicated that Ca
2+
/calmodulin-dependent protein kinase II (CaM kinase II) plays a critical role in mediating this response. Immunocytochemical staining with an anti-CaM kinase II antibody confirmed the expression of CaM kinase II in cultured bovine aortic endothelial cells. H
2
O
2
induced autophosphorylation of CaM kinase II and increased the activity of the enzyme, as assessed by an in-gel kinase assay. A specific inhibitor for CaM kinase II, KN93, and a calmodulin antagonist, W-7, attenuated eNOS induction by H
2
O
2
. Further studies have indicated that janus kinase 2 is important in mediating increased eNOS expression in response to H
2
O
2
and likely is downstream from CaM kinase II. In conclusion, these data provide the first evidence that CaM kinase II plays a critical role in endothelial redox signaling. Regulation of eNOS via this pathway may represent an important vascular adaptation to oxidant stress.
Lipoprotein Size and Atherosclerosis Susceptibility in

Apoe

−/−
and

Ldlr

−/−
Mice
Authors: Véniant Murielle M. , Withycombe Shannon , Young Stephen G.
Published: September 2007

Two hypercholesterolemic mouse models, the apo-E–deficient mouse (
Apoe
−/−
) and the LDL receptor–deficient mouse (
Ldlr
−/−
), have been used extensively as animal models of atherogenesis. Total plasma cholesterol levels in chow-fed
Apoe
−/−
mice are much higher than in
Ldlr
−/−
mice. In a recent study, we managed to even-up the cholesterol levels in
Apoe
−/−
mice and
Ldlr
−/−
mice by making both models homozygous for the
Apob
100
(apo B-100–only) allele. On a chow diet, apo-E–deficient apo B-100–only mice (
Apoe
−/−
Apob
100/100
) and LDL receptor–deficient apo B-100–only mice (
Ldlr
−/−
Apob
100/100
) had similar total plasma cholesterol levels (≈300 mg/dL). The plasma of
Ldlr
−/−
Apob
100/100
mice contained large numbers of small lipoproteins, whereas the plasma of
Apoe
−/−
Apob
100/100
mice contained much lower levels of much larger lipoproteins. Interestingly, the
Ldlr
−/−
Apob
100/100
mice developed far more extensive atherosclerotic lesions than the
Apoe
−/−
Apob
100/100
mice. The finding of substantially more atherosclerosis in
Ldlr
−/−
Apob
100/100
mice than in
Apoe
−/−
Apob
100/100
mice, despite nearly identical cholesterol levels, suggests that large numbers of small apo B-100–containing lipoproteins are far more atherogenic than lower numbers of large apo B-100–containing lipoproteins.
Bioavailability of Vitamin E as Function of Food Intake in Healthy Subjects
Authors: Iuliano L. , Micheletta F. , Maranghi M. , Frati G. , Diczfalusy U. , Violi F.
Published: September 2007

Clinical trials with vitamin E have yielded contrasting results. In these trials, the amount of vitamin E given was different, and the compliance was not assessed in all studies. In addition, the modality of intake, ie, in relation to food, was not specified in any trial. Vitamin E is lipophilic, and its absorption is expected to be increased by food. We studied the bioavailability of vitamin E in relation to food intake and the effect on the lipid peroxide–scavenging activity of plasma and on 7β-hydroxycholesterol and 7-ketocholesterol (oxysterols) as markers of oxidant stress. Twenty healthy Italian subjects were randomly assigned to take vitamin E at 300 mg/d on an empty stomach (group A) or during dinner (group B) for 15 days. Plasma vitamin E markedly increased in group B (84%) compared with group A (29%). The lipid peroxide–scavenging activity of plasma increased significantly in group B (14%,
P
=0.005) but did not change in group A. All subjects showed very low levels of plasma oxysterols, which were not affected by vitamin E supplementation in either group. This study shows that plasma concentration of vitamin E and plasma antioxidant activity in response to oral supplementation are markedly affected by food intake. Healthy Italian subjects show very low levels of cholesterol oxidation products; these low levels are possibly related to the Mediterranean diet. To obtain maximal absorption, vitamin E must be given at meals. These data should be taken into account in clinical trials with vitamin E.
Macrophage-Specific Expression of Human Lipoprotein Lipase Accelerates Atherosclerosis in Transgenic Apolipoprotein E Knockout Mice but Not in C57BL/6 Mice
Authors: Wilson Katina , Fry Glenna L. , Chappell David A. , Sigmund Curt D. , Medh Jheem D.
Published: September 2007

Transgenic mice with macrophage-specific expression of human (hu) lipoprotein lipase (LPL) were generated to determine the contribution of macrophage LPL to atherogenesis. Macrophage specificity was accomplished with the scavenger receptor A promoter. Complete characterization demonstrated that macrophages from these mice expressed huLPL mRNA and secreted enzymatically active huLPL protein. Expression of huLPL was macrophage specific, because total RNA isolated from heart, thymus, lung, liver, muscle, and adipose tissues was devoid of huLPL mRNA. Macrophage-specific expression of huLPL did not exacerbate lesions in aortas of C57BL/6 mice even after 32 weeks on an atherosclerotic diet. However, when expressed in apolipoprotein E knockout background, the extent of occlusion in the aortic sinus region of male huLPL+ mice increased 51% (n=9 to 11,
P
<0.002) compared with huLPL− mice after they had been fed a Western diet for 8 weeks. The proatherogenic effect of macrophage LPL was confirmed in serial sections of the aorta obtained after mice had been fed a Western diet for 3 weeks. By immunohistochemical analysis, huLPL protein was detected in the lesions of huLPL+ mice but not in huLPL− mice. Our results establish that macrophage LPL accelerates atherosclerosis in male apolipoprotein E knockout mice.
Pleiotropic Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors
Authors: Takemoto Masao , Liao James K.
Published: September 2007

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins are potent inhibitors of cholesterol biosynthesis. Several large clinical trials have demonstrated the beneficial effects of statins in the primary and secondary prevention of coronary heart disease. However, the overall clinical benefits observed with statin therapy appear to be greater than what might be expected from changes in lipid profile alone, suggesting that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol-independent or “pleiotropic” effects of statins involve improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation. Many of these pleiotropic effects of statins are mediated by their ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules. In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall.
Transforming Growth Factor-β1 Inhibits Macrophage Cholesteryl Ester Accumulation Induced by Native and Oxidized VLDL Remnants
Authors: Argmann Carmen A. , Van Den Diepstraten Caroline H. , Sawyez Cynthia G. , Edwards Jane Y. , Hegele Robert A. , Wolfe Bernard M. , Huff Murray W.
Published: September 2007

Transforming growth factor β1 (TGF-β1) is secreted by various cells, including macrophages, smooth muscle cells, and endothelial cells. TGF-β1 is present in atherosclerotic lesions, but its role in regulating macrophage foam cell formation is not understood. Hypertriglyceridemic very low density lipoprotein (VLDL) remnants (VLDL-REMs) in their native or oxidized form will induce cholesteryl ester (CE) and triglyceride (TG) accumulation in macrophages. Therefore, we examined whether TGF-β1 can modulate the macrophage uptake of native or oxidized VLDL-REMs (oxVLDL-REMs). Incubation of J774A.1 macrophages with VLDL-REMs and oxVLDL-REMs compared with control cells increased cellular CE (13- and 21-fold, respectively) and TG mass (21-and 18-fold, respectively). Preincubation with TGF-β1 before incubation with VLDL-REMs or oxVLDL-REMs significantly decreased CE (73% and 54%, respectively) and TG mass (42% and 41%, respectively). TGF-β1 inhibited the activity and expression of 2 key components needed for VLDL-REM uptake: lipoprotein lipase and low density lipoprotein receptor. TGF-β1 inhibited CE mass induced by oxVLDL-REMs in part by decreasing the expression of scavenger receptor type AI/II and CD36. Furthermore, TGF-β1 enhanced cholesterol efflux through upregulation of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Thus, TGF-β1 inhibits macrophage foam cell formation induced by VLDL-REMs or oxVLDL-REMs, which suggests an antiatherogenic role for this cytokine.
Downregulation of Angiotensin II Type 1 Receptor by Hydrophobic 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors in Vascular Smooth Muscle Cells
Authors: Ichiki Toshihiro , Takeda Kotaro , Tokunou Tomotake , Iino Naoko , Egashira Kensuke , Shimokawa Hiroaki , Hirano Katsuya , Kanaide Hideo , Takeshita Akira
Published: September 2007

Abstract
—

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, so-called statins, reduce the relative risk of a major coronary event by lowering the serum cholesterol level. In addition, statins may confer beneficial effects by cholesterol-lowering independent mechanisms, which are incompletely characterized. Because angiotensin II (Ang II) plays crucial roles in the pathogenesis of cardiovascular diseases, we examined the effect of statins on the expression of the Ang II type 1 receptor (AT
1
-R) in cultured vascular smooth muscle cells (VSMCs). Cerivastatin and fluvastatin reduced the AT
1
-R mRNA and the AT
1
-R protein levels; however, pravastatin lacked this effect. Cerivastatin and fluvastatin suppressed the AT
1
-R promoter activity measured by luciferase assay but did not affect AT
1
-R mRNA stability, suggesting that the suppression occurs at the transcriptional level. Coincubation of VSMCs with mevalonate or geranylgeranyl pyrophosphate but not with farnesyl pyrophosphate reversed the cerivastatin-induced AT
1
-R downregulation. Overexpression of dominant-negative Rho A also suppressed AT
1
-R mRNA expression. Treatment with cerivastatin for 24 hours reduced the calcium response of VSMCs to Ang II. Taken together, statins downregulate AT
1
-R expression through a mevalonate-dependent, geranylgeranyl pyrophosphate-dependent, and Rho A-dependent manner and attenuate the biological function of Ang II. Downregulation of AT
1
-R may contribute to the cholesterol-independent beneficial effect of statins on the cardiovascular system.
Elevated C-Reactive Protein Constitutes an Independent Predictor of Advanced Carotid Plaques in Dyslipidemic Subjects
Authors: Blackburn Robert , Giral Philippe , Bruckert Eric , André Jean-Michel , Gonbert Sophie , Bernard Maguy , Chapman M. John , Turpin Gérard
Published: September 2007

Inflammation plays a key role in the physiopathology of atherosclerosis. C-reactive protein (CRP) has been found to predict cardiac events in healthy subjects and in patients with coronary heart disease. However, the relationship between CRP and subclinical atherosclerosis is not well established. We examined the potential relationship between CRP and common carotid artery intima-media thickness and carotid plaques in dyslipidemic subjects. Dyslipidemic patients (n=1051) were recruited for the study. All patients had a complete clinical examination and systematically underwent ultrasonographic evaluation of the extracranial carotid arteries on a duplex system. The serum concentration of CRP was measured by using a sensitive immunoradiometric assay. In a univariate model, a strong positive relationship was found between CRP and the severity of carotid stenosis (
P
<0.0001). In multivariate analysis, the association between CRP and the degree of carotid atherosclerosis remained significant for advanced plaques (
P
=0.0007) in male subjects only. Significant correlations were found between CRP and body mass index (
P
<0.0001) and between CRP and other markers associated with the metabolic syndrome. In this large dyslipidemic population, elevated CRP is an independent predictor of advanced carotid plaques in male subjects. Body mass index and other markers of the metabolic syndrome (HDL cholesterol, triglycerides, diabetes, and high blood pressure) are significant determinants of CRP levels in this population.
Immune Mechanisms in Atherosclerosis
Authors: Hansson Göran K.
Published: September 2007

Atherosclerosis is an inflammatory disease. Its lesions are filled with immune cells that can orchestrate and effect inflammatory responses. In fact, the first lesions of atherosclerosis consist of macrophages and T cells. Unstable plaques are particularly rich in activated immune cells, suggesting that they may initiate plaque activation. We have seen a rapid increase in the understanding of the mechanisms that govern the recruitment, differentiation, and activation of immune cells in atherosclerosis. Experimental research has identified several candidate antigens, and there are encouraging data suggesting that immune modulation as well as immunization can reduce the progression of the disease. This review provides an overview of our current understanding of the role of immune mechanisms in atherosclerosis.
Contribution of Nitric Oxide to Arterial Pressure and Heart Rate Variability in Rats Submitted to High-Sodium Intake
Authors: Lacchini Silvia , Ferlin Elton L. , Moraes Ruy S. , Ribeiro Jorge P. , Irigoyen Maria Claudia
Published: September 2007

The aim of this study was to determine the contribution of NO to arterial pressure and heart rate variability in normotensive rats subjected to high sodium intake. Arterial pressure, heart rate, and arterial pressure and heart rate variability, baroreflex sensitivity, and pressure responsiveness were measured in male Wistar rats treated for 6 weeks (control and high sodium [1%] intake groups), before and after acute NO synthesis blockade. After treatment, no changes were observed in arterial pressure or heart rate. Arterial pressure variability was increased after sodium intake; however, heart rate variability and baroreflex sensitivity were not modified in high-sodium rats. NO synthase blockade increased arterial pressure in both groups but was higher in the high-sodium group (from 110±5 to 162±1.5 mm Hg) compared with the control group (from 109±6.7 to 144±10 mm Hg). The increase in arterial pressure was accompanied by a decrease in heart rate (from 354±28 to 303±25 bpm in control rats and from 380±34 to 298±30 bpm in high-sodium rats). NO synthase blockade increased the tachycardic response to sodium nitroprusside in high-sodium rats. Arterial pressure variability, evaluated by a nonlinear method (3D return maps), showed a larger reduction in response to NO synthase inhibition in the high-sodium group (from 162±26 to 34.8±8.6 for general index of beat-to-beat blood pressure variability) than in the control group (from 58±9.6 to 36±4.7 for general index of beat-to-beat blood pressure variability). Heart rate variability, evaluated by the SD of the R-R intervals, was not changed in control rats but was increased by NO synthase inhibition in the high-sodium rats (from 9.5±0.2 to 21.9±1.7 milliseconds). These findings suggest an important role for increased NO production in adaptation to high-sodium intake. The increase in NO system sensitivity in high-sodium intake may contribute to changes in the autonomic nervous system regulating heart rate and, especially, arterial pressure variability.
Renal Dopamine System
Authors: Carey Robert M.
Published: September 2007

All of the components of a complete dopamine system are present within the kidney, where dopamine acts as a paracrine substance in the control of sodium excretion. Dopamine receptors can be divided into D
1
-like (D
1
and D
5
) receptors that stimulate adenylyl cyclase and D
2
-like (D
2
, D
3
, and D
4
) receptors that inhibit adenylyl cyclase. All 5 receptor subtypes are expressed in the kidney, albeit in low copy. Dopamine is synthesized extraneuronally in proximal tubule cells, exported from these cells largely into the tubule lumen, and interacts with D
1
-like receptors to inhibit the Na
+
-H
+
exchanger and Na
+
,K
+
-ATPase, decreasing tubule sodium reabsorption. During moderate sodium surfeit, dopamine tone at D
1
-like receptors accounts for ≈50% of sodium excretion. In experimental and human hypertension, 2 renal dopaminergic defects have been described: (1) decreased renal generation of dopamine and (2) a D
1
receptor-G protein coupling defect. Both defects lead to renal sodium retention, and each may play an important role in the pathophysiology of essential hypertension.
Angiotensin II AT
1A
Receptor Antisense Lowers Blood Pressure in Acute 2-Kidney, 1-Clip Hypertension
Authors: Galli Sara M. , Phillips M. Ian
Published: September 2007

Abstract
—

— To test the effectiveness of antisense oligonucleotides targeted to the angiotensin type 1A (AT
1A
) receptor mRNA on blood pressure reduction, the 2-kidney, 1-clip (2K1C) Goldblatt model of hypertension was studied in the acute phase of hypertension, when the peripheral renin-angiotensin system is overactive. A single injection of AT
1A
receptor antisense oligodeoxynucleotides significantly reduced systolic blood pressure for a period of 8 days in 2K1C rats after clipping, from 157.5±5 mm Hg on day 7 to 141.3±3.0 mm Hg on day 15 after clipping (
P
<0.01). The AT
1A
receptor antisense oligonucleotide labeled with fluorescein shows that the antisense oligonucleotide at 24 hours was taken up into aorta, mesenteric artery, liver, kidney glomeruli, and medulla, remaining up to 6 days. The AT
1A
receptor number in fmol/g tissue was significantly decreased after AT
1A
receptor antisense oligonucleotide treatment in the dorsal aorta, mesenteric artery, renal cortex, and renal medulla (
P
<0.05) compared with that of the AT
1A
receptor-scrambled antisense oligonucleotide control-treated group. The data clearly demonstrate a prolonged antihypertensive effect of AT
1A
receptor antisense oligonucleotide in the 2K1C renovascular model of hypertension when it is administered intravenously in a single low dose (0.33 mg/kg
−1
). It also shows that the AT
1A
receptor antisense oligonucleotide is actively taken up by AT
1A
target tissues and that there is a significant decrease in receptor density. We conclude that in the acute phase of 2K1C hypertension, antisense to AT
1A
receptor decreases AT
1A
receptor density, which attenuates the vascular vasoconstrictive effects of high plasma angiotensin II levels and in the kidney elicits natriuresis. The decrease in renal AT
1A
receptor density may also lead to sodium loss and reduction of extracellular volume.
Blood Pressure Control and Benefits of Antihypertensive Therapy
Authors: Ruilope Luis M. , Schiffrin Ernesto L.
Published: September 2007

Abstract
—

— This article debates the important question of whether blood pressure lowering alone is responsible for the benefits accrued from antihypertensive therapy as demonstrated in many multicenter randomized clinical trials with different antihypertensive agents or whether there is evidence that some agents have special properties that result in benefits that go beyond those resulting from lowering blood pressure. Over the past ≥30 years, it has been demonstrated beyond any doubt that lowering blood pressure in severe forms of hypertension, and more recently in systolic and even mild hypertension, will result in reduced incidence of stroke and slower progression of heart and renal failure. These effects have been easier to demonstrate in sicker patients, because enough end points may be counted in the 3 to 5 years that these clinical trials last. However, risk attributable to high blood pressure comes, to a greater degree, from the much larger group of hypertensive individuals who have less severe forms of hypertension. Blood pressure lowering offers less protection from coronary heart disease, which is highly prevalent in hypertensive patients, than from stroke. With the introduction of agents such as renin-angiotensin system inhibitors or calcium channel blockers, it has been demonstrated that hypertensive vascular remodeling and endothelial dysfunction may be corrected. It has therefore been suggested that benefits beyond blood pressure lowering may be achieved with the use of specific drugs to lower blood pressure. Although some evidence suggests that this may be the case, it is difficult to extrapolate from mechanistic studies to prevention of hard end points in outcome trials and vice versa. The question remains for the time being largely unanswered.
Hyperkalemia, Renal Failure, and Converting-Enzyme Inhibition
Authors: García Néstor H. , Baigorria Sandra T. , Juncos Luis I.
Published: September 2007

Abstract
—

— Hyperkalemia is widely viewed as a common complication of ACE inhibition in azotemic patients. These renal failure patients are the patients who benefit most from ACE inhibition. Because we could not confirm this notion after a retrospective evaluation of 236 azotemic patients, we studied 2 models of renal mass reduction. In the first, we did a 5/6 nephrectomy (Nx) on rats and studied them 2 weeks after surgery (before chronic renal changes had developed). A second group was studied 16 weeks after Nx, once chronic renal failure was established. Rats in both models were treated with quinapril in drinking water. After baseline evaluation, we challenged them either by a high-K
+
diet or by blocking aldosterone receptors. We found that although quinapril blocked the K
+
-induced increase in aldosterone, serum K
+
levels and K
+
balance were maintained before and during high K
+
intake or during simultaneous spironolactone administration. We conclude that in hemodynamically stable rats with reduced renal mass and renal dysfunction, the administration of an ACE inhibitor does not cause severe hyperkalemia.
Enhanced Contraction to 5-Hydroxytryptamine Is Not Due to “Unmasking” of 5-Hydroxytryptamine1BReceptors in the Mesenteric Artery of the Deoxycorticosterone Acetate–Salt Rat
Authors: Banes Amy K.L. , Watts Stephanie W.
Published: September 2007

5-Hydroxytryptamine1B(5-HT1B) receptors have been implicated in mediating arterial contraction to 5-HT. Additionally, the 5-HT1Breceptor has been reported to be “unmasked” by depolarizing stimuli. We hypothesized that 5-HT1Breceptors in arteries from hypertensive animals, arteries reported to have a depolarized resting membrane potential in smooth muscle cells, are unmasked and participate in the supersensitivity observed to 5-HT in hypertension. We used the isolated tissue bath apparatus and examined the response of superior mesenteric arteries from normotensive sham and hypertensive deoxycorticosterone acetate (DOCA)–salt rats. The 5-HT1Bagonists CP93129 and sumatriptan (10−9to 10−5mol/L) caused a maximal contraction (50±12% of phenylephrine [10−5mol/L] contraction) in arteries from DOCA-salt rats; no contraction was observed in arteries from normotensive rats. The 5-HT1Breceptor antagonist GR55562 (100 nmol/L) inhibited both the 5-HT– (4-fold rightward shift) and CP93129-induced (11-fold rightward shift) contractions in mesenteric arteries from hypertensive DOCA-salt rats. In other experiments, arteries from normotensive rats were incubated with 15 mmol/L KCl, as a depolarizing stimulus, and then exposed to 5-HT and CP93129. In the presence of KCl, a small leftward shift to 5-HT was observed. However, the presence of a depolarizing stimulus was unable to produce changes in the 5-HT maximal response to resemble that of arteries from DOCA-salt rats, nor was contraction to CP93129 observed. These data support the conclusions that 5-HT1Breceptors mediate contraction in mesenteric arteries from hypertensive rats and that this enhanced response to 5-HT is not due to membrane depolarization alone.
Predictors of Target Organ Damage in Hypertensive Blacks and Whites
Authors: El-Gharbawy Areeg H. , Kotchen Jane Morley , Grim Clarence E. , Kaldunski Mary , Hoffmann Raymond G. , Pausova Zdenka , Gaudet Daniel , Gossard Francis , Hamet Pavel , Kotchen Theodore A.
Published: September 2007

The purpose of this study was to evaluate the association of the insulin resistance syndrome with both blood pressure and target organ damage in blacks and whites with essential hypertension. Eighty-two black and 63 white French Canadian patients were studied. None had diabetes, and antihypertensive medications had been discontinued for ≥1 week. Measurements included 24-hour blood pressure monitoring, fasting plasma lipids, insulin sensitivity determined with the Bergman minimal model, echocardiogram, microalbumin excretion, and inulin and lithium clearances. Compared with the white French Canadians, black patients had an attenuated nighttime reduction in blood pressure (
P
<0.02), increased cardiac dimensions (
P
<0.001), greater microalbumin excretion (
P
<0.05), increased inulin clearance (indicative of glomerular hyperfiltration;
P
<0.001), and decreased lithium clearance (indicative of increased sodium reabsorption in the proximal tubule;
P
<0.001). Blood pressure levels were not related to insulin resistance; although in blacks, the nighttime reduction in systolic blood pressure was inversely related to fasting plasma insulin (
r
=−0.18,
P
<0.04). In a stepwise multivariate analysis (including blood pressure levels and components of the insulin resistance syndrome as independent variables), race was the strongest predictor of left ventricular mass (
r
=0.53,
P
<0.000), relative wall thickness (
r
=0.49,
P
<0.000), and both inulin (
r
=0.53,
P
<0.000) and lithium (
r
=0.41,
P
<0.000) clearances. Nighttime systolic blood pressure was also a significant determinant of concentric left ventricular hypertrophy (
r
=0.37,
P
<0.000). In blacks, microalbumin excretion was related to insulin resistance. These observations are consistent with the hypothesis that there is a genetic contribution to cardiac hypertrophy, glomerular hyperfiltration, and sodium retention in blacks with essential hypertension.
Stroke Prognosis and Abnormal Nocturnal Blood Pressure Falls in Older Hypertensives
Authors: Kario Kazuomi , Pickering Thomas G. , Matsuo Takefumi , Hoshide Satoshi , Schwartz Joseph E. , Shimada Kazuyuki
Published: September 2007

It remains uncertain whether abnormal dipping patterns of nocturnal blood pressure influence the prognosis for stroke. We studied stroke events in 575 older Japanese patients with sustained hypertension determined by ambulatory blood pressure monitoring (without medication). They were subclassified by their nocturnal systolic blood pressure fall (97 extreme-dippers, with ≥20% nocturnal systolic blood pressure fall; 230 dippers, with ≥10% but <20% fall; 185 nondippers, with ≥0% but <10% fall; and 63 reverse-dippers, with <0% fall) and were followed prospectively for an average duration of 41 months. Baseline brain magnetic resonance imaging (MRI) disclosed that the percentages with multiple silent cerebral infarct were 53% in extreme-dippers, 29% in dippers, 41% in nondippers, and 49% in reverse-dippers. There was a J-shaped relationship between dipping status and stroke incidence (extreme-dippers, 12%; dippers, 6.1%; nondippers, 7.6%; and reverse-dippers, 22%), and this remained significant in a Cox regression analysis after controlling for age, gender, body mass index, 24-hour systolic blood pressure, and antihypertensive medication. Intracranial hemorrhage was more common in reverse-dippers (29% of strokes) than in other subgroups (7.7% of strokes,
P
=0.04). In the extreme-dipper group, 27% of strokes were ischemic strokes that occurred during sleep (versus 8.6% of strokes in the other 3 subgroups,
P
=0.11). In conclusion, in older Japanese hypertensive patients, extreme dipping of nocturnal blood pressure may be related to silent and clinical cerebral ischemia through hypoperfusion during sleep or an exaggerated morning rise of blood pressure, whereas reverse dipping may pose a risk for intracranial hemorrhage.
Linkage of Left Ventricular Contractility to Chromosome 11 in Humans
Authors: Arnett Donna K. , Devereux Richard B. , Kitzman Dalane , Oberman Al , Hopkins Paul , Atwood Larry , Dewan Andrew , Rao D.C.
Published: September 2007

Impaired left ventricular (LV) contractility is a major cause of cardiovascular death, especially congestive heart failure. The identification of susceptibility genes that contribute to impaired LV contractility may uncover mechanisms underlying LV contractile impairment and the development of congestive heart failure. The Hypertension Genetic Epidemiology Network (HyperGEN) collected echocardiographic measurements of myocardial contractility in a large biethnic sample of hypertensive siblings (390 blacks and 398 whites in 179 and 165 sibships, respectively). All participants expressed hypertension before age 60 years, and the mean age of siblings was 52 years in blacks and 61 years in whites. We adjusted myocardial contractility for gender, age, and age
2
, and we calculated standardized residuals separately for men and women in both ethnic groups. We conducted multipoint variance components linkage analysis using GENEHUNTER2 and 387 anonymous markers (CHCL8 marker set). We found evidence for significant linkage to a microsatellite marker, D11S1993 (lod, 3.93 in blacks), ≈54 cM from the tip of the short arm of chromosome 11, that accounted for 72% of the phenotypic variation in LV contractility. A chromosome 22 locus showed suggestive evidence for linkage (lod, 2.83 in whites and 1.15 in blacks). The chromosome 11 peak coincides with the region containing myosin-binding protein C. Mutations in this gene are linked to familial hypertrophic cardiomyopathy. Our results show strong evidence for linkage of a region of chromosome 11 with LV contractility in blacks and suggest that an important gene for impaired LV contractility is harbored in this region.
Localization of the Endothelin System in Aldosterone-Producing Adenomas
Authors: Egidy Giorgia , Baviera Erno , Ciuffo Gladys , Corvol Pierre , Pinet Florence
Published: September 2007

Endothelin-1 (ET-1) could play a role in the regulation of aldosterone secretion of the human adrenal gland. The presence of the endothelin-converting enzyme 1 (ECE-1) and ET-1 suggests that there is a local ET system in the adrenal cortex, but the in situ synthesis of ET-1 remains to be confirmed. The cellular distribution of the whole ET system was evaluated in 20 cases of aldosterone-producing adenomas. Polymerase chain reaction studies gave strong signals for ECE-1 mRNA and the mRNAs for endothelin type A (ETA) and B (ETB) receptors and faint signals for prepro–ET-1 mRNA. In situ hybridization showed ETAreceptors scattered throughout the adenoma, in both secretory cells and vascular structures (score, +). There were more ETBreceptors (score, ++), but they were restricted mainly to the endothelium. ECE-1 mRNA and protein were ubiquitous and abundant in secretory cells (score, +++) and vascular structures (score, ++); the enzyme was active on big ET-1. There was no prepro–ET-1 mRNA in the cortex, except in the thickened precapillary arterioles present in only 30% of the aldosterone-producing adenomas studied. ET-1 immunoreactivity was detected in vascular structures (score, +), probably bound to receptors, suggesting that ET-1 has an endocrine action. The low concentrations of ET-1 could also indicate that it acts in a paracrine-autocrine fashion to control adrenal blood flow. The discrepancy between the concentrations of ECE-1 and its substrate suggests that ECE-1 has another role in the adrenal secretory cells. Our data indicate that ET probably is not a primary cause of the development or maintenance of the adenoma.
Angiotensin II via Activation of Type 1 Receptor Upregulates Expression of Endoglin in Human Coronary Artery Endothelial Cells
Authors: Li Dayuan , Chen Hongjiang , Mehta Jawahar L.
Published: September 2007

Transforming growth factor-β1 and its subtype receptor endoglin are key components in angiogenesis. We explored the role of angiotensin (Ang) II in the expression of endoglin and the underlying intracellular signaling mechanism in human coronary artery endothelial cells. Incubation of cells with Ang II upregulated endoglin expression in a concentration- and time-dependent manner (maximal effect with 10−6mol/L Ang II at 24 hours). The Ang II type 1 receptor blocker losartan, but not the type 2 receptor blocker PD 123,319, completely blocked the effect of Ang II. In parallel experiments, the mitogen-activated protein kinase inhibitor PD 098,059 fully inhibited the effect of Ang II on the expression of endoglin. Incubation of endothelial cells with Ang II also increased the expression of transforming growth factor-β1 and -β2 receptors and simultaneously decreased the levels of transforming growth factor-β1. These effects of Ang II were also attenuated by losartan. We propose that Ang II via its type 1 receptor activation modulates the expression of transforming growth factor-β1 receptors in human coronary endothelial cells. The activation of mitogen-activated protein kinase plays an important role in this process. These observations provide a new clue regarding the regulatory effect of Ang II on vascular remodeling after injury.
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Upregulate Inducible NO Synthase Expression and Activity in Vascular Smooth Muscle Cells
Authors: Kolyada Alexey Y. , Fedtsov Alexandre , Madias Nicolaos E.
Published: September 2007

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase ameliorate atherosclerosis by both cholesterol-dependent and cholesterol-independent mechanisms. We examined whether HMG-CoA reductase inhibitors affect the expression and activity of inducible NO synthase (iNOS) in cultured rat aortic vascular smooth muscle (VSM) cells. Atorvastatin (34 to 68 μmol/L) markedly increased nitrite production, an increase that was essentially abrogated by the NO synthase inhibitor
N
G
-monomethyl-
l
-arginine (500 μmol/L). Activity of iNOS, determined by the conversion of
l
-arginine to
l
-citrulline, increased 9-fold after atorvastatin treatment. Western blot and semiquantitative reverse transcriptase-polymerase chain reaction revealed that atorvastatin (34 to 68 μmol/L) strongly upregulated iNOS protein and mRNA levels, respectively. These concentrations of atorvastatin did not cause cytotoxicity, as judged by the cell survival rate. Similarly, simvastatin and lovastatin (34 μmol/L) caused robust upregulation of the iNOS protein level. Transfection experiments demonstrated that the −1034- to 88-bp human iNOS promoter was strongly induced by atorvastatin (34 μmol/L). Electromobility and supershift assays using a nuclear factor-κB (NF-κB) consensus oligonucleotide and nuclear extracts from VSM cells as well as transfection studies using an NF-κB reporter plasmid suggested that the transcriptional activation of the iNOS gene by atorvastatin is not mediated via the NF-κB pathway. We conclude that HMG-CoA reductase inhibitors potently upregulate iNOS expression and activity in VSM cells, at least in part, by transcriptional mechanisms that do not depend on transcription factor NF-κB. These effects might have important implications for the impact of HMG-CoA reductase inhibitors on atherosclerosis.
Gangliosides GM1 and GM2 Induce Vascular Smooth Muscle Cell Proliferation via Extracellular Signal-Regulated Kinase 1/2 Pathway
Authors: Gouni-Berthold Ioanna , Seul Claudia , Ko Yon , Hescheler Jürgen , Sachinidis Agapios
Published: September 2007

Gangliosides, sialic acid-containing glycophospholipids, accumulate in atherosclerotic vessels and appear to regulate the proliferation of various cell types. Furthermore, vascular smooth muscle cell (VSMC) proliferation is associated with the development and progression of cardiovascular diseases. To demonstrate whether gangliosides are able to modulate the VSMC growth, the effect of gangliosides GM1, GM2, and GM3 on cell DNA synthesis and cell number has been examined. Moreover, we investigated possible intracellular mechanisms by which GM1 and GM2 elicit their mitogenic effects. Stimulation of VSMCs with GM1 and GM2 resulted in a dose-dependent increase in DNA synthesis and cell number, whereas GM3 caused a decrease in DNA synthesis. GM1 and GM2 (50 μmol/L) stimulate phosphorylation of extracellular signal-regulated kinases (ERKs) 1 and 2 and phosphorylation of the c-Jun N-terminal kinase (JNK), with a maximum at 15 minutes, but they do not have an effect on the phosphorylation of p38 mitogen-activated protein kinase (MAPK). GM3 (50 μmol/L), on the other hand, does not stimulate any of the 3 aforementioned MAPKs. Pretreatment of the cells with 20 μmol/L PD 098,059 caused a complete inhibition of ERK1/2 and JNK MAPK, whereas pretreatment with a Ras (farnesyl transferase) inhibitor did not abrogate the GM1- and GM2-induced ERK1/2 phosphorylation. Furthermore, GM1 and GM2 did not activate Raf-1 kinase. Interestingly, pretreatment of VSMCs with 100 nmol/L pertussis toxin resulted in a complete inhibition of the ERK1/2 phosphorylation. Finally, the GM1- and GM2-induced increase in cell number was significantly inhibited by PD 098,059. We may conclude that GM1 and GM2 stimulate ERK1/2 via a pertussis toxin-sensitive Gi-coupled receptor through a Raf-1 kinase-independent pathway. Moreover, the GM1- and GM2-induced VSMC growth is ERK1/2 dependent.
High-Meat, Low-Carbohydrate Diet in Pregnancy
Authors: Shiell Alistair W. , Campbell-Brown Mary , Haselden Soraya , Robinson Sian , Godfrey Keith M. , Barker David J.P.
Published: September 2007

To examine the hypothesis that a high–animal protein, low-carbohydrate diet in pregnancy is associated with raised blood pressure in the adult offspring, we performed a follow-up study of 626 men and women in Motherwell, Scotland, whose mothers’ food intake had been recorded during pregnancy. The mothers had taken part in a dietary intervention in which they were advised to eat 1 lb (0.45 kg) of red meat per day and to avoid carbohydrate-rich foods during pregnancy. The offspring were followed up at age 27 to 30 years, and their systolic and diastolic blood pressures were measured. Women who reported greater consumption of meat and fish in the second half of pregnancy had offspring with higher systolic blood pressure in adult life (regression coefficient, 0.19 mm Hg per portion per week; 95% confidence interval, 0.04 to 0.35;
P
=0.02). High maternal consumption of fish, but not meat, was associated with higher diastolic blood pressure in the offspring (regression coefficient, 1.00 mm Hg per portion per week; 95% confidence interval, 0.18 to 1.82;
P
=0.02). These associations were independent of maternal blood pressure, body size, and smoking habits during pregnancy. Although we cannot exclude confounding by maternal saturated fat or salt intake, the findings support those of a study in Aberdeen showing higher blood pressure in men and women whose mothers had eaten a high–animal protein, low-carbohydrate diet in late pregnancy. These associations may reflect the metabolic stress imposed on the mother by an unbalanced diet in which high intakes of essential amino acids are not accompanied by the nutrients required to utilize them.
Fibrinogen and Preclinical Echocardiographic Target Organ Damage
Authors: Palmieri Vittorio , Celentano Aldo , Roman Mary J. , de Simone Giovanni , Lewis Michael R. , Best Lyle , Lee Elisa T. , Robbins David C. , Howard Barbara V. , Devereux Richard B.
Published: September 2007

Relations of fibrinogen to preclinical target organ damage, such as left ventricular hypertrophy, systolic dysfunction, and increased arterial stiffness while accounting for traditional risk factors, are unknown in a population-based sample free of clinically overt coronary heart disease. Therefore, we studied clinical and echocardiographic characteristics of 2709 American Indians participating in the Strong Heart Study without symptomatic atherosclerosis. The study sample was divided into tertiles of fibrinogen (cut-points, 3.24 and 3.83 g/L). Mean age, body mass index, proportion of women, and prevalences of hypertension and diabetes increased from the first to third tertile of fibrinogen. After adjustment for covariates, systolic and pulse pressures did not significantly differ among tertiles of fibrinogen, whereas diastolic pressure was slightly lower in the third than in lower tertiles of fibrinogen. HDL cholesterol was lower and plasma creatinine and urinary albumin/creatinine ratio was higher in the third tertile of fibrinogen. Left ventricular mass index, pulse pressure/stroke index, an estimate of arterial stiffness, and cardiac index were higher and left ventricular systolic function and total peripheral resistance were lower in the third than in two lower tertiles of fibrinogen independent of major covariates. In multiple regression analyses, left ventricular mass and pulse pressure/stroke index were positively associated with, and stress-corrected midwall shortening negatively associated with fibrinogen, independent of major covariates. Participants with fibrinogen >3.83 g/L were more likely to have at least 1 preclinical cardiovascular abnormality such as left ventricular hypertrophy, elevated arterial stiffness, or systolic myocardial dysfunction independent of covariates including renal dysfunction (adjusted odds ratio, 1.38;
P
<0.001). Thus, in a population sample of adults without clinically overt coronary heart disease, elevated fibrinogen is an independent correlate of prognostically relevant cardiovascular target organ damage.