bluuebunny/crossref_metadata_2025 huggingface dataset:
The renal retinoid system: time-dependent activation in experimental glomerulonephritis
Authors: Liebler Sabine , Überschär Birgit , Kübert Helen , Brems Stefanie , Schnitger Anna , Tsukada Miki , Zouboulis Christos C. , Ritz Eberhard , Wagner Jürgen
Published: February 2004

Retinoids reduce renal damage in rat experimental glomerulonephritis. It is unknown, however, how local and systemic retinoid pathways respond to renal injury. We used a rat model of artificially induced acute anti-Thy1.1-nephritis (THY-GN). We examined the extrarenal and glomerular expression of the retinol (RoDH) and retinal (RalDH) dehydrogenases 1 and 2 as well as the expression of the retinoic acid (RAR) and retinoid X (RXR) receptor subtypes α, β, and γ. Furthermore, we investigated serum and glomerular retinoid concentration patterns. On days 3, 7, and 14, we compared nonnephritic rats (control group; CON) to THY-GN rats with respect to systolic blood pressure and glomerular cell count per cross section. Systolic blood pressure and glomerular cell count were significantly higher in THY-GN rats on days 7 and 14 ( P < 0.001). We found a 60% reduction in expression levels for retinoid receptors and dehydrogenases in nephritic glomeruli on day 3, but a threefold increase on day 7 ( P < 0.001 vs. CON). The same applies to RARα protein. Hepatic expression of retinoid receptors was not influenced. On day 14, glomerular expression levels for retinoid receptors and retinoid-metabolizing enzymes had returned to a normal level, glomerular cell count being still increased. Administering 13- cis retinoic acid (isotretinoin) lowered blood pressure and glomerular cell count in nephritic rats but failed to influence the glomerular expression of retinoid receptors or retinoid-metabolizing enzymes. Our data document a stimulation of glomerular retinoid-synthesizing enzymes and expression of retinoid receptors in the early repair phase of THY-GN, suggesting activation of this system in acute renal disease.
PPARα ligand protects during cisplatin-induced acute renal failure by preventing inhibition of renal FAO and PDC activity
Authors: Li Shenyang , Wu Pengfei , Yarlagadda Padma , Vadjunec Nicole M. , Proia Alan D. , Harris Robert A. , Portilla Didier
Published: February 2004

Previous studies demonstrated that during cisplatin-induced acute renal failure, there is a significant reduction in proximal tubule fatty acid oxidation. We now report on the effects of peroxisome proliferator-activated receptor-α (PPARα) ligand Wy-14643 (WY) on the abnormalities of medium chain fatty acid oxidation and pyruvate dehydrogenase complex (PDC) activity in kidney tissue of cisplatin-treated mice. Cisplatin causes a significant reduction in mRNA levels and enzyme activity of mitochondrial medium chain acyl-CoA dehydrogenase (MCAD). PPARα ligand WY ameliorated cisplatin-induced acute renal failure and prevented cisplatin-induced reduction of mRNA levels and enzyme activity of MCAD. In contrast, in cisplatin-treated PPARα null mice, WY did not protect kidney function and did not reverse cisplatin-induced decreased expression of MCAD. Cisplatin inhibited renal PDC activity before the development of acute tubular necrosis, and PDC inhibition was reversed by pretreatment with PPARα agonist WY. Cisplatin also induced increased mRNA and protein levels of pyruvate dehydrogenase kinase-4 (PDK4), and PPARα ligand WY prevented cisplatin-induced increased expression of PDK4 protein levels in wild-type mice. We conclude that PPARα agonists have therapeutic potential for cisplatin-induced acute renal failure. Use of PPARα ligands prevents acute tubular necrosis by ameliorating cisplatin-induced inhibition of two distinct metabolic processes, MCAD-mediated fatty acid oxidation and PDC activity.
Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model
Authors: Hashimoto Naoko , Maeshima Yohei , Satoh Minoru , Odawara Masahiro , Sugiyama Hitoshi , Kashihara Naoki , Matsubara Hiroaki , Yamasaki Yasushi , Makino Hirofumi
Published: February 2004

Angiotensin II mediates the progression of renal disease through the type 1 receptor (AT1R). Recent studies have suggested that type 2 receptor (AT2R)-mediated signaling inhibits cell proliferation by counteracting the actions of AT1R. The aim of the present study was to determine the effect of AT2R overexpression on glomerular injury induced by ⅚ nephrectomy (⅚Nx). AT2R transgenic mice (AT2-Tg), overexpressing AT2R under the control of α-smooth muscle actin (α-SMA) promoter, and control wild-type mice (Wild) were subjected to ⅚Nx. In AT2-Tg mice, the glomerular expression of AT2R was upregulated after ⅚Nx. Urinary albumin excretion at 12 wk after ⅚Nx was decreased by 33.7% in AT2-Tg compared with Wild mice. Glomerular size in AT2-Tg mice was significantly smaller than in Wild mice after ⅚Nx (93.1 ± 3.0 vs. 103.3 ± 1.8 μm; P < 0.05). Immunohistochemistry revealed significant decreases in glomerular expression of platelet-derived growth factor-BB chain (PDGF-BB) and transforming growth factor-β1(TGF-β1) in AT2-Tg with ⅚Nx compared with Wild mice. Urinary excretion of nitric oxide metabolites was increased 2.5-fold in AT2-Tg compared with Wild mice. EMSA showed that activation of early growth response gene-1, which induces the transcription of PDGF-BB and TGF-β1, was decreased in AT2-Tg mice. These changes in AT2-Tg mice at 12 wk after ⅚Nx were blocked by the AT2R antagonist PD-123319. Taken together, our findings suggest that AT2R-mediated signaling may protect from glomerular injuries induced by ⅚Nx and that overexpression of AT2R may serve as a potential therapeutic strategy for glomerular disorders.
Differential regulation of branched-chain α-ketoacid dehydrogenase kinase expression by glucocorticoids and acidification in LLC-PK1-GR101 cells
Authors: Wang Xiaonan , Price S. Russ
Published: February 2004

Acidosis and glucocorticoids (GC) are two catabolic signals associated with chronic renal disease. Previously, we reported that these signals stimulate branched-chain amino acid (BCAA) oxidation in renal tubule cells by increasing both the amount and activation state of branched-chain α-ketoacid dehydrogenase (BCKD). Activation of the BCKD complex could result from decreased expression of BCKD kinase, which inhibits BCKD by phosphorylating its E1α subunit. To investigate this possibility, we examined how dexamethasone and acidification (pH 7.0) influence BCKD kinase expression in LLC-PK1-GR101 cells. Dexamethasone, a synthetic GC, decreased BCKD kinase protein by 65% ( P < 0.05 vs. control), whereas a low pH (i.e., pH 7.0) decreased the amount of kinase by 71% ( P < 0.05 vs. control). Either GC or acidification reduced BCKD kinase mRNA by 46% ( P < 0.05 vs. control), but the two signals together did not reduce kinase mRNA more than either signal alone. To examine the mechanism(s) leading to lower kinase mRNA, kinase transcription was evaluated by transiently transfecting LLC-PK1-GR101 cells with BCKD kinase promoter-luciferase mini-genes containing ∼3.5 kb of proximal rat kinase promoter. GC, but not acidification, decreased luciferase activity 42% ( P < 0.05 vs. control). Nuclear run-on assays confirmed that GC decrease kinase mRNA by attentuating its transcription. Thus two catabolic signals associated with renal failure, GC and acidification, reduce BCKD kinase expression by different mechanisms. These responses lead to an increase in the activation state of BCKD and a resulting acceleration of BCAA degradation.
ROMK is required for expression of the 70-pS K channel in the thick ascending limb
Authors: Lu Ming , Wang Tong , Yan Qingshang , Wang Wenhui , Giebisch Gerhard , Hebert Steven C.
Published: February 2004

Apical potassium recycling is crucial for salt transport by the thick ascending limb (TAL). Loss-of-function mutations in the K channel, ROMK (Kir1.1; KCNJ1), cause Bartter syndrome, a genetically heterogeneous disorder characterized by severe reduction in salt absorption by the TAL, Na wasting, polyuria, and hypokalemic alkalosis. ROMK(-/-) null mice exhibit a Bartter phenotype and lack the small-conductance (30-pS) apical K channel (SK) in the TAL. However, a distinct 70-pS K channel can also significantly contribute to the apical conductance of TAL. We now examine the effect of ROMK deletion on the functional expression of the 70-pS K channel in the TAL. Functional expression of the 70-pS K channel was low [average channel acitivty ( NPo) = 0.02] in ROMK(+/+) mice on a control K diet but increased to 0.27 by high-K intake for 2 wk. In contrast, the high-K diet decreased NPo of SK by ∼30%, from 2.04 to 1.44. In ROMK heterozygous (+/-) mice on a control K diet, SK activity was about one-half of that observed in ROMK(+/+) mice (0.95 vs. 2.04). The high-K diet also reduced SK activity in ROMK(+/-) mice by ∼40% (from 0.95 to 0.55) but increased NPo of the 70-pS K channel from 0 to 0.09 in ROMK(+/-) mice. This corresponds to ∼30% of channel activity ( NPo = 0.27) observed in ROMK(+/+) mice. Neither the 70-pS nor the 30-pS K channels were observed in TAL cells from ROMK(-/-) mice on either the normal or high-K diets. Thus functional expression of the 70-pS K channel is enhanced by increasing dietary K and requires expression of ROMK. It is likely that ROMK forms a critical subunit of the 70-pS K channel, accounting for the loss of apical K secretory channel activity in ROMK Bartter syndrome.
Genetic architecture of fast- and slow-twitch skeletal muscle weight in 200-day-old mice of the C57BL/6J and DBA/2J lineage
Authors: Lionikas A. , Blizard D. A. , Vandenbergh D. J. , Glover M. G. , Stout J. T. , Vogler G. P. , McClearn G. E. , Larsson L.
Published: February 2004

The aim of the study was to explore the genetic architecture influencing weight of fast- and slow-twitch skeletal muscles. The weights of the slow-twitch soleus, the mixed gastrocnemius, the fast-twitch tibialis anterior (TA), and extensor digitorum longus (EDL) muscles were 11–34% greater ( P < 0.001) in 200-day-old C57BL/6J (B6) than in DBA/2J (D2) mice. Male muscles were 13–28% larger than female ( P < 1 × 10−5, no strain by sex interaction). The sex-related difference in muscle weight, however, varied significantly among the 23 derivative BXD recombinant inbred (RI) strains (strain by sex interaction for soleus, P < 0.01; TA, P < 1 × 10−4; EDL, not significant; and gastrocnemius, P < 0.001). Quantitative trait loci (QTL) affecting muscle weight were mapped in an F2 intercross of B6 and D2 mice (B6D2F2) and BXD RIs. A total of 10 autosomal, muscle-specific, but not muscle-type-specific, QTL, explaining a total of 5.4, 7.7, 22.9, and 8.6% of phenotypic variance for soleus, TA, EDL, and gastrocnemius muscles, respectively, were found across chromosomes 1 (Chr 1), 2, 3 (female-specific), 5 (two), 6, 7, 8, and 9 in B6D2F2 mice. The QTL on Chr 8 for EDL and the female-specific QTL on Chr 3 for gastrocnemius muscles were statistically significant, but the remaining QTL were at the suggestive level of statistical significance. Ten QTL on Chr 1, 2, 4, 5, 7, 8, 14, 17 (two), and 19 were identified in BXD RIs. Half of the QTL in BXD RIs had pleiotropic effects and were at the suggestive level of significance (except for the significant QTL for gastrocnemius muscle on Chr 17). The B6D2F2 nominated QTL on Chr 8 for EDL weight was validated in BXD RIs ( P < 0.03). Support intervals for the QTL on Chr 1 and 5 overlapped between B6D2F2 and BXD RIs. An epistatic interaction between markers on Chr 1 and 17 affected gastrocnemius weight in BXD RIs. The interaction was not, however, validated in the B6D2F2 population. Our results indicate that the differences in muscle weight in the B6 and D2 segregating populations were the outcome of a polygenic system, with each factor contributing a small amount to the phenotypic variance and the genetic architecture affecting muscle weight was muscle specific, but not muscle-type specific, and in some instances sex specific.
On linear difference equations over rings and modules
Authors: Abuhlail Jawad Y.
Published: February 2004

We develop a coalgebraic approach to the study of solutions of
linear difference equations over modules and rings. Some known
results about linearly recursive sequences over base fields are
generalized to linearly (bi)recursive (bi)sequences of modules
over arbitrary commutative ground rings.
Human Apolipoprotein A-IV Reduces Secretion of Proinflammatory Cytokines and Atherosclerotic Effects of a Chronic Infection Mimicked by Lipopolysaccharide
Authors: Recalde Delia , Ostos Maria A. , Badell Edgar , Garcia-Otin Angel-Luis , Pidoux Josette , Castro Graciela , Zakin Mario M. , Scott-Algara Daniel
Published: February 2004

Objective—

Expression of human apolipoprotein (h-apo) A-IV in apoE-deficient (apoE
0
) mice (h-apoA-IV/E
0
) reduces susceptibility to atherosclerosis. Chronic infection mimicked by exposure to lipopolysaccharide (LPS) increases the size of atherosclerosis lesions in apoE
0
mice. Thus, we used h-apoA-IV/E
0
mice to determine whether h-apoA-IV plays a protective role after LPS administration.

Methods and Results—

We injected apoE
0
, h-apoA-IV/E
0
, and C57Bl/6 (wild-type) mice intraperitoneally with either LPS or phosphate-buffered saline (PBS) every week for 10 weeks. Atherosclerotic lesions were significantly smaller in h-apoA-IV/E
0
mice treated with LPS than in their apoE
0
counterparts. The titers of IgG2a and IgG2b autoantibodies to oxidized low-density lipoprotein (LDL) were higher in the LPS-group of h-apoA-IV/E
0
mice than in apoE
0
mice, suggesting that the Th1 response is stronger in the presence of h-apoA-IV. Lymphocytes from the blood, liver, spleen, and thymus of h-apoA-IV/E
0
mice treated with LPS produced less IL-4, INF-γ, and TNF-α proinflammatory cytokines than their apoE
0
counterparts. Furthermore, we demonstrated that recombinant h-apoA-IV blocks the LPS-induced stimulation of monocytes.

Conclusions—

The expression of h-apoA-IV in apoE
0
mice reduces the susceptibility to atherogenesis and decreases the secretion of proinflammatory cytokines after LPS administration.
Combined Blockade of the Chemokine Receptors CCR1 and CCR5 Attenuates Chronic Rejection
Authors: Yun James J. , Whiting David , Fischbein Michael P. , Banerji Anamika , Irie Yoshihito , Stein Daniel , Fishbein Michael C. , Proudfoot Amanda E.I. , Laks Hillel , Berliner Judith A. , Ardehali Abbas
Published: February 2004

Background—

Chemokine-chemokine receptor interaction and the subsequent recruitment of T-lymphocytes to the graft are early events in the development of chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV). In this study, we sought to determine whether blockade of chemokine receptors CCR1 and CCR5 with Met-RANTES affects the development of CAV in a murine model.

Methods and Results—

B6.CH-2
bm12
strain donor hearts were transplanted heterotopically into wild-type C57BL/6 mice (myosin heavy chain II mismatch). Recipients were treated daily with either Met-RANTES or vehicle starting on postoperative day 4 and were euthanized on postoperative days 24 and 56. We found that Met-RANTES significantly reduced intimal thickening in this model of chronic rejection and that Met-RANTES markedly decreased the infiltration of CD4 and CD8 T lymphocytes and MOMA-2
+
monocytes/macrophages into transplanted hearts. Met-RANTES also suppressed the ex vivo and in vitro proliferative responses of recipient splenocytes to donor antigens. Finally, Met-RANTES treatment was associated with a marked reduction in RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels in the donor hearts.

Conclusions—

Antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuates CAV development in vivo by reducing mononuclear cell recruitment to the transplanted heart, proliferative responses to donor antigens, and intragraft RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and may serve as potential therapeutic targets.
Increased Myocardial Dysfunction After Ischemia-Reperfusion in Mice Lacking Glucose-6-Phosphate Dehydrogenase
Authors: Jain Mohit , Cui Lei , Brenner Daniel A. , Wang Bo , Handy Diane E. , Leopold Jane A. , Loscalzo Joseph , Apstein Carl S. , Liao Ronglih
Published: February 2004

Background—

Free radical injury contributes to cardiac dysfunction during ischemia-reperfusion. Detoxification of free radicals requires maintenance of reduced glutathione (GSH) by NADPH. The principal mechanism responsible for generating NADPH and maintaining GSH during periods of myocardial ischemia-reperfusion remains unknown. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, generates NADPH in a reaction linked to the de novo production of ribose. We therefore hypothesized that G6PD is essential for maintaining GSH levels and protecting the heart during ischemia-reperfusion injury.

Methods and Results—

Susceptibility to myocardial ischemia-reperfusion injury was determined in Langendorff-perfused hearts isolated from wild-type mice (WT) and mice lacking G6PD (G6PD
def
) (20% of WT myocardial G6PD activity). During global zero-flow ischemia, cardiac function was similar between WT and G6PD
def
hearts. On reperfusion, however, cardiac relaxation and contractile performance were greatly impaired in G6PD
def
myocardium, as demonstrated by elevated end-diastolic pressures and decreased percent recovery of developed pressure relative to WT hearts. Contractile dysfunction in G6PD
def
hearts was associated with depletion of total glutathione stores and impaired generation of GSH from its oxidized form. Increased ischemia-reperfusion injury in G6PD
def
hearts was reversed by treatment with the antioxidant MnTMPyP but unaffected by supplementation of ribose stores.

Conclusions—

These results demonstrate that G6PD is an essential myocardial antioxidant enzyme, required for maintaining cellular glutathione levels and protecting against oxidative stress-induced cardiac dysfunction during ischemia-reperfusion.
Ventricular Fibrillation Scaling Exponent Can Guide Timing of Defibrillation and Other Therapies
Authors: Menegazzi James J. , Callaway Clifton W. , Sherman Lawrence D. , Hostler David P. , Wang Henry E. , Fertig Kristofer C. , Logue Eric S.
Published: February 2004

Background—

The scaling exponent (ScE) of the ventricular fibrillation (VF) waveform correlates with duration of VF and predicts defibrillation outcome. We compared 4 therapeutic approaches to the treatment of VF of various durations.

Methods and Results—

Seventy-two swine (19.5 to 25.7 kg) were randomly assigned to 1 of 9 groups (n=8 each). VF was induced and left untreated until the ScE reached 1.10, 1.20, 1.30, or 1.40. Animals were treated with either immediate countershock (IC); 3 minutes of CPR before the first countershock (CPR); CPR for 2 minutes, then drugs given with 3 more minutes of CPR before the first shock (CPR-D); or drugs given at the start of CPR with 3 minutes of CPR before the first shock (Drugs+CPR). Return of spontaneous circulation (ROSC) and 1-hour survival were analyzed with χ
2
and Kaplan-Meier survival curves. IC was effective when the ScE was low but had decreasing success as the ScE increased. No animals in the 1.30 or 1.40 groups had ROSC from IC (0 of 16). CPR did not improve first shock outcome in the 1.20 CPR group (3 of 8 ROSC). Kaplan-Meier survival analyses indicated that IC significantly delayed time to ROSC in both the 1.3 (
P
=0.0006) and the 1.4 (
P
=0.005) groups.

Conclusions—

VF of brief to moderate duration is effectively treated by IC. When VF is prolonged, as indicated by an ScE of 1.3 or greater, IC was not effective and delayed time to ROSC. The ScE can help in choosing the first intervention in the treatment of VF.
Valsartan Restores Sarcoplasmic Reticulum Function With No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure
Authors: Okuda Shinichi , Yano Masafumi , Doi Masahiro , Oda Tetsuro , Tokuhisa Takahiro , Kohno Masateru , Kobayashi Shigeki , Yamamoto Takeshi , Ohkusa Tomoko , Matsuzaki Masunori
Published: February 2004

Background—

Although angiotensin II receptor blockade is considered to be useful for the treatment of human heart failure, little beneficial hemodynamic effect has been shown in some experimental failing hearts. In this study, we assessed the effect of an angiotensin II receptor blocker, valsartan, on sarcoplasmic reticulum (SR) function, defectiveness of which is a major pathogenic mechanism in heart failure.

Methods and Results—

SR vesicles were isolated from dog left ventricular muscle (normal or exposed to 4-week rapid ventricular pacing with or without valsartan). In the untreated and valsartan-treated paced dogs, cardiac function showed similar deterioration (compared with before pacing). However, both the density of β-receptors and the contractile response to dobutamine were greater in the valsartan-treated paced dogs than in the untreated paced dogs. In untreated paced hearts, the ryanodine receptor was protein kinase A–hyperphosphorylated, showed an abnormal Ca
2+
leak, and had a decreased amount of ryanodine receptor–bound FKBP12.6. No such phenomena were seen in the valsartan-treated paced hearts. Both the SR Ca
2+
uptake function and the amount of Ca
2+
-ATPase were decreased in the untreated failing SR, but both were restored in the valsartan-treated SR.

Conclusions—

During the development of pacing-induced heart failure, valsartan preserved the density of β-receptors and concurrently restored SR function without improving resting cardiac function.
Clinical and Angiographic Predictors of Restenosis After Stent Deployment in Diabetic Patients
Authors: West Nick E.J. , Ruygrok Peter N. , Disco Clemens M.C. , Webster Mark W.I. , Lindeboom Wietze K. , O’Neill William W. , Mercado Nestor F. , Serruys Patrick W.
Published: February 2004

Background—

Restenosis and consequent adverse cardiac events are increased in diabetics undergoing percutaneous coronary intervention. Use of intracoronary stents may ameliorate such risks; however, factors influencing the likelihood of restenosis after stent deployment in this high-risk patient subgroup are unknown.

Methods and Results—

We retrospectively analyzed all stented diabetic patients in 16 studies of percutaneous coronary intervention, all of which underwent core angiographic analysis at Cardialysis, Rotterdam. Univariate and multivariate analyses, with 37 clinical and angiographic variables, compared those with and without restenosis and predicted restenosis rates calculated through the use of reference charts derived from angiographic data. Within the studies, 418 of 3090 (14%) stented patients with 6-month angiographic follow-up had diabetes. Restenosis (≥50% diameter stenosis at follow-up) occurred in 550 of 2672 (20.6%) nondiabetic and 130 of 418 (31.1%) diabetic patients (
P
<0.001). Univariate predictors of restenosis in diabetics were smaller vessel reference diameter (RD) (
P
<0.001), smaller minimal luminal diameter before stenting (
P
=0.01), smaller minimal luminal diameter and percent diameter stenosis after stenting (
P
<0.001,
P
=0.04), greater stented length of vessel (
P
<0.001), and reduced body mass index (BMI) (
P
=0.04). With the use of multivariate analysis, only smaller RD (
P
=0.003), greater stented length of vessel (
P
=0.04), and reduced BMI (
P
=0.04) were associated with restenosis. Reference charts demonstrated an incremental risk of restenosis that appears solely dependent on vessel RD.

Conclusions—

Restenosis after stent deployment is significantly increased in diabetic patients. Vessel caliber, stented length of vessel, and lower BMI are predictors of in-stent restenosis in patients with diabetes. Furthermore, vessel caliber affected the predicted risk of restenosis incrementally.
Volumetric Analysis of In-Stent Intimal Hyperplasia in Diabetic Patients Treated With or Without Abciximab
Authors: Chaves Áurea J. , Sousa Amanda G.M.R. , Mattos Luiz A. , Abizaid Alexandre , Staico Rodolfo , Feres Fausto , Centemero Marinella , Tanajura Luiz F. , Abizaid Andrea , Pinto Ibraim , Maldonado Galo , Seixas Ana , Costa Marco A. , Paes Ângela , Mintz Gary S. , Sousa J. Eduardo
Published: February 2004

Background—

In diabetic patients in the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial, abciximab reduced target vessel revascularization by ≈50% compared with placebo. Whether this is a result of a lower restenosis rate caused by inhibition of intimal hyperplasia remains to be defined.

Methods and Results—

The purpose of this study was to determine whether abciximab at the time of stent implantation would reduce in-stent intimal hyperplasia measured by intravascular ultrasound at 6-month follow-up in type 2 diabetics. Ninety-six diabetic patients (96 lesions) who underwent elective stent implantation for a de novo lesion in a native coronary artery were randomly assigned to receive abciximab or no abciximab. In-stent intimal hyperplasia volume, expressed as percentage of stent volume, did not differ between groups: 41.3±21.0% for those treated with abciximab versus 40.5±18.3% for those treated without abciximab (
P
=0.9). There were also no significant differences in angiographic minimal luminal diameter at follow-up (1.74±0.69 versus 1.66±0.63 mm;
P
=0.5), late loss (1.03±0.63 versus 1.07±0.58 mm;
P
=0.7), restenosis rate (17.8% versus 22.9%;
P
=0.5), or cumulative incidence of major adverse cardiac events at 12 months (19.1% versus 20.4%;
P
=0.9).

Conclusions—

Six-month intravascular ultrasound volumetric analysis showed that abciximab, at the time of coronary stent implantation, was not associated with a reduction of in-stent intimal hyperplasia in diabetic patients.
Anti-Inflammatory and Profibrinolytic Effect of Insulin in Acute ST-Segment–Elevation Myocardial Infarction
Authors: Chaudhuri Ajay , Janicke David , Wilson Michael F. , Tripathy Devjit , Garg Rajesh , Bandyopadhyay Arindam , Calieri Janeen , Hoffmeyer Debbie , Syed Tufail , Ghanim Husam , Aljada Ahmad , Dandona Paresh
Published: February 2004

Background—

The clinical benefits of insulin previously observed in acute ST-segment–elevation myocardial infarction (STEMI) may be partially explained by an anti-inflammatory effect. We assessed this potential effect of insulin in STEMI patients treated with fibrinolytics.

Methods and Results—

Thirty-two patients receiving reteplase were randomly assigned infusions of either insulin at 2.5 U/h, dextrose, and potassium (GIK) or normal saline and potassium (C) for 48 hours. Plasma concentrations of high-sensitivity C-reactive protein (CRP), serum amyloid A (SAA), plasminogen activator inhibitor-1 (PAI-1), creatine kinase (CK), and CK-MB were measured at baseline and sequentially for 48 hours. Total p47
phox
protein in mononuclear cells was measured in a subgroup of 13 subjects. Baseline CRP and SAA were significantly increased (2- to 4-fold) at 24 and 48 hours in each group (
P
<0.01). However, in the insulin group, there was a significant (
P
<0.05) attenuation of the absolute rise in concentration of CRP and SAA from baseline. The absolute increase of CRP and SAA was reduced by 40% (CRP) and 50% (SAA) at 24 hours and at 48 hours compared with the control group. The absolute increase in PAI-1 from baseline and the percentage increase in p47
phox
over 48 hours were significantly (
P
<0.05) lower in the insulin-treated group. CK-MB peaked earlier and tended to be lower in insulin-treated subjects, especially in patients with inferior MI.

Conclusions—

Insulin has an anti-inflammatory and profibrinolytic effect in patients with acute MI. These effects may contribute to the clinical benefits of insulin in STEMI.
Lipoprotein-Associated Phospholipase A
2
, High-Sensitivity C-Reactive Protein, and Risk for Incident Coronary Heart Disease in Middle-Aged Men and Women in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Ballantyne Christie M. , Hoogeveen Ron C. , Bang Heejung , Coresh Josef , Folsom Aaron R. , Heiss Gerardo , Sharrett A. Richey
Published: February 2004

Background—

Measuring C-reactive protein (CRP) has been recommended to identify patients at high risk for coronary heart disease (CHD) with low LDL cholesterol (LDL-C). Lipoprotein-associated phospholipase A
2
(Lp-PLA
2
) is a proinflammatory enzyme associated primarily with LDL.

Methods and Results—

In a prospective, case cohort study in 12 819 apparently healthy middle-aged men and women in the Atherosclerosis Risk in Communities study, the relation between Lp-PLA
2
, CRP, traditional risk factors, and risk for CHD events over a period of ≈6 years was examined in a proportional hazards model, stratified by LDL-C. Lp-PLA
2
and CRP levels were higher in the 608 cases than the 740 noncases. Both Lp-PLA
2
and CRP were associated with incident CHD after adjustment for age, sex, and race with a hazard ratio of 1.78 for the highest tertile of Lp-PLA
2
and 2.53 for the highest category of CRP versus the lowest categories. Lp-PLA
2
correlated positively with LDL-C (
r
=0.36) and negatively with HDL-C (
r
=−0.33) but not with CRP (
r
=−0.05). In a model adjusted for traditional risk factors including LDL-C, the association of Lp-PLA
2
with CHD was attenuated and not statistically significant. For individuals with LDL-C below the median (130 mg/dL), Lp-PLA
2
and CRP were both significantly and independently associated with CHD in fully adjusted models. For individuals with LDL-C <130 mg/dL, those with both Lp-PLA
2
and CRP levels in the highest tertile were at the greatest risk for a CHD event.

Conclusions—

Lp-PLA
2
and CRP may be complementary in identifying individuals at high CHD risk who have low LDL-C.
Cytochrome P-450 Inhibition Attenuates Hypertension Induced by Reductions in Uterine Perfusion Pressure in Pregnant Rats
Authors: Llinás Maria T. , Alexander Barbara T. , Capparelli Maria F. , Carroll Mairead A. , Granger Joey P.
Published: February 2004

The present study tested the hypothesis that cytochrome P-450 (CYP) metabolites of arachidonic acid (AA) are involved in mediating hypertension and renal vasoconstriction during chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats. 1-aminobenzotriazole (ABT), a CYP enzyme inhibitor (25 mg/kg per day), or vehicle (saline 0.9%) was administered for 7 days to normal pregnant (NP) rats and to pregnant rats with chronic RUPP. RUPP rats infused with vehicle showed significantly (
P
<0.01) higher mean arterial pressure (MAP) (130±2 versus 106±1 mm Hg), renal vascular resistance (RVR) (22.6±1.8 versus 16.3±1.1 mm Hg/mL per minute) and lower (
P
<0.05) glomerular filtration rate (GFR) (1.6±0.1 versus 2.3±0.1 mL/min) than NP rats. ABT decreased (
P
<0.01) MAP in RUPP rats (111±1 mm Hg), whereas it had no effect in NP rats (108±2 mm Hg). CYP inhibition also attenuated the differences in renal hemodynamics observed between NP and RUPP rats. After treatment with ABT, RVR and GFR were similar in RUPP rats (19.3±1.5 mm Hg/mL per minute and 2.0±0.2 mL/min, respectively) and NP rats (16.3±2.4 mm Hg/mL per minute and 2.4±0.2 mL/min). The effects of CYP enzymes inhibitor in RUPP rats were associated with a reduction (
P
<0.05) of 20-HETE formation (32%) and a decreased (
P
<0.05) expression (33%) of CYP4A protein in renal cortex. In contrast, renal epoxygenase activity did not change in these animals. These results suggest that 20-HETE contributes to hypertension and renal vasoconstriction induced by chronic RUPP in pregnant rats.
AT1 Receptor Blocker Added to ACE Inhibitor Provides Benefits at Advanced Stage of Hypertensive Diastolic Heart Failure
Authors: Yoshida Junichi , Yamamoto Kazuhiro , Mano Toshiaki , Sakata Yasushi , Nishikawa Nagahiro , Nishio Mayu , Ohtani Tomohito , Miwa Takeshi , Hori Masatsugu , Masuyama Tohru
Published: February 2004

Diastolic heart failure (DHF) has become a social burden; however, evidences leading to its therapeutic strategy are lacking. This study investigated effects of addition of angiotensin II type 1 receptor blocker (ARB) to angiotensin-converting enzyme inhibitor (ACEI) at advanced stage of DHF in hypertensive rats. Dahl salt-sensitive rats fed 8% NaCl diet from age 7 weeks served as DHF model, and those fed a normal chow served as control. The DHF model rats were arbitrarily assigned to 3 treatment regimens at age 17 weeks: ACEI (temocapril 0.4 mg/kg per day), combination of ACEI (temocapril 0.2 mg/kg per day) with ARB (olmesartan 0.3 mg/kg per day), or placebo. At age 17 weeks, this model represents progressive ventricular hypertrophy and fibrosis, relaxation abnormality, and myocardial stiffening. Data were collected at age 20 weeks. As compared with the monotherapy with ACEI, the addition of ARB induced more prominent suppression of ventricular hypertrophy and fibrosis, leading to suppression of myocardial stiffening, improvement of relaxation, and inhibition of hemodynamic deterioration. Such benefits were associated with greater decreases in reactive oxygen species (ROS) generation, macrophage infiltration, and gene expression of transforming growth factor (TGF)-β
1
and interleukin (IL)-1β, but not with changes in gene expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-α. Thus, ARB added to ACEI provides more benefits as compared with ACEI alone in DHF when initiated at an advanced stage. The additive effects are likely provided through more prominent suppression of ROS generation and inflammatory changes without effects on expression of MCP-1 and TNF-α.
Androgens Are Necessary for the Development of Fructose-Induced Hypertension
Authors: Song Dongzhe , Arikawa Emi , Galipeau Denise , Battell Mary , McNeill John H.
Published: February 2004

Hyperinsulinemia and insulin resistance are closely associated with hypertension in humans and in animal models. Gender differences have been found in the development of hypertension in fructose-fed rats. The objectives of the present study were, first, to clarify whether androgens are required in the development of hyperinsulinemia, insulin resistance, and hypertension in fructose-fed rats, and second, to determine if cyclooxygenase-1 and cyclooxygenase-2 are also increased in the arteries of these rats. Male rats were gonadectomized or sham-operated and fed a 60% fructose diet beginning at age 7 weeks. Blood pressure was measured by a tail-cuff method, and an oral glucose tolerance test was performed to assess insulin sensitivity after 8 weeks of fructose feeding. Cyclooxygenase-1 and cyclooxygenase-2 mRNA expression was also assessed in the thoracic aortae and mesenteric arteries. Gonadectomy prevented hypertension from developing in the fructose-fed rats, but hyperinsulinemia and insulin resistance developed. There was an increase in cyclooxygenase-2 expression in the thoracic aortae and mesenteric arteries of the fructose-fed sham-operated rats while the expression of cyclooxygenase-1 remained unchanged. Gonadectomy prevented the mRNA overexpression of vascular cyclooxygenase-2 in the fructose-fed rats. These results suggest that the presence of androgens is necessary for the development of fructose-induced hypertension. Androgens apparently act as a link between hyperinsulinemia/insulin resistance and hypertension in fructose-hypertensive rats. Furthermore, an increase in the expression of cyclooxygenase-2 is implicated in the development of hypertension. The mechanisms involved require further study.
Overlap Between Whites and Blacks in Response to Antihypertensive Drugs
Authors: Sehgal Ashwini R.
Published: February 2004

On average, whites and blacks differ in their response to specific antihypertensive drugs. These differences are often highlighted in reviews and practice guidelines. However, there is wide variation in drug-associated changes in blood pressure within each race. The goal of this meta-analysis is to quantitate how often whites and blacks have similar responses to specific antihypertensive drugs. Computerized searches of MEDLINE (1983 to March 2003) and manual searches of references listed in identified articles were performed. Studies were included if they provided race-specific changes in blood pressure. Fifteen studies with a total of 9307 white subjects and 2902 black subjects were analyzed. For drug-associated changes in diastolic blood pressure, the mean difference between whites and blacks ranged from 0.6 to 3.0 mm Hg while the standard deviation within each race ranged from 5.0 to 10.1 mm Hg. The percentage of whites and blacks with similar drug-associated changes in diastolic blood pressure was 90% (95% confidence interval: 81 to 99) for diuretics, 90% (95% CI: 83 to 97) for β-blockers, 95% (95% CI: 92 to 98) for calcium channel blockers, and 81% (95% CI: 76 to 86) for angiotensin converting enzyme inhibitors. The percentage of whites and blacks with similar drug-associated changes in systolic blood pressure ranged from 83% to 93%. In conclusion, the majority of whites and blacks have similar responses to commonly used antihypertensive drugs. Clinical decisions to use a specific drug should be based on other considerations such as efficacy in individual patients, compelling indications, and cost.
Essential Role for Smad3 in Regulating MCP-1 Expression and Vascular Inflammation
Authors: Feinberg Mark W. , Shimizu Koichi , Lebedeva Maria , Haspel Richard , Takayama Kiyoshi , Chen Zhiping , Frederick Joshua P. , Wang Xiao-Fan , Simon Daniel I. , Libby Peter , Mitchell Richard N. , Jain Mukesh K.
Published: February 2004

Transforming growth factor (TGF)-β
1
is a pleiotropic growth factor with known inhibitory effects on immune cell activation. However, the specific mechanism(s) and in vivo significance of the effectors of TGF-β
1
modulation in the context of vascular inflammation are not well characterized. The chemokine monocyte chemoattractant protein (MCP)-1 is critical for the recruitment of macrophages in inflammatory disease states. In this study, we provide definitive evidence that the ability of TGF-β
1
to inhibit MCP-1 expression is mediated via its effector Smad3. Adenoviral overexpression of Smad3 potently repressed inducible expression of endogenous MCP-1. Conversely, TGF-β
1
inhibition of cytokine-mediated induction of MCP-1 expression was completely blocked in Smad3-deficient macrophages. Consistent with this impaired response, cardiac allografts in Smad3-deficient mice developed accelerated intimal hyperplasia with increased infiltration of adventitial macrophages expressing MCP-1. Previous studies show that MCP-1 inducibility is regulated by an AP-1 complex composed of c-Jun/c-Fos heterodimers. We demonstrate that the inhibitory effect of Smad3 occurs via a novel antagonistic effect of Smad3 on AP-1 DNA-protein binding and activity. Thus, Smad3 plays an essential role in modulating vascular inflammation characteristic of transplant-associated arteriopathy, is important in regulating MCP-1 expression, and plays a critical role in the ability of TGF-β
1
to repress stimuli from a major inflammatory signaling pathway.
p21

Cip1

Levels Differentially Regulate Turnover of Mature Endothelial Cells, Endothelial Progenitor Cells, and In Vivo Neovascularization
Authors: Brühl Tom , Heeschen Christopher , Aicher Alexandra , Jadidi Amir S. , Haendeler Judith , Hoffmann Jörg , Schneider Michael D. , Zeiher Andreas M. , Dimmeler Stefanie , Rössig Lothar
Published: February 2004

p21

Cip1

(p21) controls cell cycle progression and apoptosis in mature endothelial cells (ECs) and regulates size and cycling of the hematopoietic progenitor cell pool. Because circulating endothelial progenitor cells (EPCs) contribute to postnatal neovascularization in addition to mature ECs, we investigated the regulation of ECs and EPCs in p21-deficient mice. Mature aortic EC proliferation was increased in homozygous p21
−/−
and heterozygous p21
+/−
mice, in which p21 protein levels are reduced to one third of wild-type (WT). In contrast, apoptosis sensitivity was increased by 3.5-fold only in p21
−/−
, but not in p21
+/−
mice. Consistently, in vivo apoptosis of ECs within areas of neovascularization was elevated in p21
−/−
but not in p21
+/−
mice. EPC numbers were elevated 2-fold in p21
−/−
mice compared with WT (
P
<0.001), and clonal expansion capacity of EPCs was increased from 25±4 (WT) to 57±8 colony-forming units in p21
−/−
mice (
P
<0.005). EPC numbers and expansion were likewise increased in p21
+/−
mice. As the integrative endpoint, in vivo neovascularization reflecting all p21-affected parameters was increased over WT only in p21
+/−
(
P
<0.001), but not in p21
−/−
mice. In conclusion, reduced p21 protein levels of mice lacking one p21 allele are associated with increased proliferation of ECs and EPCs, whereas survival of ECs to apoptotic stimuli in vitro and in vivo is not impaired. Under these conditions, neovascularization was increased. In contrast, complete p21 deficiency did not result in an increased neovascularization despite increased mature EC and EPC proliferation. This may be due to the sensitization of ECs against apoptosis.
Higher Levels of Interleukin-6 Are Associated With Lower Echogenicity of Carotid Artery Plaques
Authors: Yamagami Hiroshi , Kitagawa Kazuo , Nagai Yoji , Hougaku Hidetaka , Sakaguchi Manabu , Kuwabara Keisuke , Kondo Kimito , Masuyama Tohru , Matsumoto Masayasu , Hori Masatsugu
Published: February 2004

Background and Purpose—

Echo-lucent carotid plaques can be fragile and vulnerable to rupture, representing a risk factor for ischemic stroke. Given the studies showing that elevated levels of circulating inflammatory markers are predictive of cardiovascular events, we sought to determine whether higher levels of serum interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) are associated with lower echogenicity of carotid plaques.

Methods—

The study comprised 246 patients who had carotid atherosclerotic plaques as evidenced by ultrasound. Using acoustic densitometry, we quantified the echogenicity of the largest plaque in each patient by integrated backscatter analysis. Serum IL-6 and hsCRP levels were determined in all patients.

Results—

Both log-transformed IL-6 and hsCRP concentrations were negatively correlated with carotid plaque echogenicity (
r
=−0.28,
P
<0.001, and
r
=−0.14,
P
<0.05, respectively). When traditional atherosclerotic risk factors, plaque thickness, and medication use were controlled for, IL-6 levels were inversely associated with plaque echogenicity (β=−0.21,
P
<0.01), whereas such an association was of borderline significance for hsCRP (β=−0.12,
P
=0.06).

Conclusions—

Higher IL-6 levels, in addition to hsCRP levels, appear to be associated with lower echogenicity of carotid plaques, suggesting a link between inflammation and potential risk of plaques.
Systemic Thrombolysis With Recombinant Tissue Plasminogen Activator and Tirofiban in Acute Middle Cerebral Artery Occlusion
Authors: Straub Stefan , Junghans Ulrich , Jovanovic Verica , Wittsack Hans J. , Seitz Rüdiger J. , Siebler Mario
Published: February 2004

Background and Purpose—

In acute ischemic stroke, thrombolytic treatment with recombinant tissue plasminogen activator (rtPA) is limited by a concomitant activation of the coagulatory system, leading to incomplete or delayed reperfusion, microcirculatory disturbances, or even repeated vessel occlusions. Our pilot study sought to assess the therapeutic potential of a new treatment strategy combining rtPA at reduced dosages with a platelet glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitory agent in acute middle cerebral artery occlusion.

Methods—

Nineteen patients suffering from acute middle cerebral artery occlusion (Thrombolysis in Myocardial Infarction [TIMI] flow grade 0 to 1) underwent combined intravenous thrombolytic treatment using rtPA at reduced dosages and the GPIIb/IIIa antagonist tirofiban. Stroke MRI (diffusion- and perfusion-weighted imaging) and MR angiography were performed at baseline and between days 1 and 2 after treatment. Clinical scores (National Institutes of Health Stroke Scale and modified Rankin Scale) were assessed at baseline and after 1 week.

Results—

Middle cerebral artery recanalization (TIMI flow grade 2 and 3) occurred in 13 of 19 patients (68%). The ischemic lesion on follow-up MRI was significantly smaller in patients with recanalization compared with those without recanalization (
P
=0.001). Only patients with recanalization improved neurologically (
P
<0.001). Because no symptomatic hemorrhage was observed, the power of our study to detect a symptomatic bleeding rate of ≥8% was at least 80%.

Conclusions—

Combined thrombolysis with a GPIIb/IIIa antagonist and rtPA at reduced dosages is promising but cannot be recommended for general use before prospective randomized clinical trials are completed.
Mechanisms and implications of phosphoinositide 3-kinase δ in promoting neutrophil trafficking into inflamed tissue
Authors: Puri Kamal D. , Doggett Teresa A. , Douangpanya Jason , Hou Yonghao , Tino William T. , Wilson Tim , Graf Thomas , Clayton Elizabeth , Turner Martin , Hayflick Joel S. , Diacovo Thomas G.
Published: February 2004

The phosphoinositide 3-kinase (PI3K) catalytic subunit p110δ is expressed in neutrophils and is thought to play a role in their accumulation at sites of inflammation by contributing to chemoattractant-directed migration. We report here that p110δ is present in endothelial cells and participates in neutrophil trafficking by modulating the proadhesive state of these cells in response to tumor necrosis factor α (TNFα). Specifically, administration of the selective inhibitor of PI3Kδ, IC87114, to animals reduced neutrophil tethering to and increased rolling velocities on cytokine-activated microvessels in a manner similar to that observed in mice deficient in p110δ. These results were confirmed in vitro as inhibition of this isoform in endothelium, but not neutrophils, diminished cell attachment in flow. A role for PI3Kδ in TNFα-induced signaling is demonstrated by a reduction in Akt-phosphorylation and phosphatidylinositol-dependent kinase 1 (PDK1) enzyme activity upon treatment of this cell type with IC87114. p110δ expressed in neutrophils also contributes to trafficking as demonstrated by the impaired movement of these cells across inflamed venules in animals in which this catalytic subunit was blocked or genetically deleted, results corroborated in transwell migration assays. Thus, PI3Kδ may be a reasonable therapeutic target in specific inflammatory conditions as blockade of its activity reduces neutrophil influx into tissues by diminishing their attachment to and migration across vascular endothelium. (Blood. 2004;103:3448-3456)
A novel plasma proteinase potentiates α2-antiplasmin inhibition of fibrin digestion
Authors: Lee Kyung N. , Jackson Kenneth W. , Christiansen Victoria J. , Chung Keun H. , McKee Patrick A.
Published: February 2004

Human α2-antiplasmin (α2AP), also known as α2-plasmin inhibitor, is the major inhibitor of the proteolytic enzyme plasmin that digests fibrin. There are 2 N-terminal forms of α2AP that circulate in human plasma: a 464-residue protein with Met as the N-terminus, Met-α2AP, and a 452-residue version with Asn as the N-terminus, Asn-α2AP. We have discovered and purified a proteinase from human plasma that cleaves the Pro12-Asn13 bond of Met-α2AP to yield Asn-α2AP and have named it antiplasmin-cleaving enzyme (APCE). APCE is similar in primary structure and catalytic properties to membrane-bound fibroblast activation protein/seprase for which a physiologic substrate has not been clearly defined. We found that Asn-α2AP becomes cross-linked to fibrin by activated factor XIII approximately 13 times faster than native Met-α2AP during clot formation and that clot lysis rates are slowed in direct proportion to the ratio of Asn-α2AP to Met-α2AP in human plasma. We conclude that APCE cleaves Met-α2AP to the derivative Asn-α2AP, which is more efficiently incorporated into fibrin and consequently makes it strikingly resistant to plasmin digestion. APCE may represent a new target for pharmacologic inhibition, since less generation and incorporation of Asn-α2AP could result in a more rapid removal of fibrin by plasmin during atherogenesis, thrombosis, and inflammatory states.