bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphoinositide Regulation of the Actin Cytoskeleton
Authors: Yin Helen L. , Janmey Paul A.
Published: January 2003

▪ Abstract  Phosphoinositides [PPIs, which collectively refer to phosphorylated derivatives of phosphatidylinositol (PI)] have a pivotal role as precursors to important second messengers and as bona fide signaling and scaffold targeting molecules. This review focuses on recent advances that elucidate how PPIs, particularly PI(4,5)P2 (PIP2), directly regulate the actin cytoskeleton in vivo by modulating the activity and targeting of actin regulatory proteins. The role of PIP2 in stimulating actin polymerization and in establishing cytoskeleton–plasma membrane linkages is emphasized. In addition, the review presents tantalizing evidence that suggests how binding of selected cytoskeletal proteins to membrane PPIs may promote PPI clustering into raft lipid microdomains, alter their accessibility to other proteins, and even distort the bilayer conformation. These actions have profound implications for many other PPI-regulated membrane functions that are beginning to be uncovered, and they suggest how PPIs can mediate crosstalk between the actin cytoskeleton and an expanding spectrum of essential cellular functions.
Dynamics of Phosphoinositides in Membrane Retrieval and Insertion
Authors: Czech Michael P.
Published: January 2003

▪ Abstract  The phosphoinositides PtdIns(4,5)P2 and PtdIns(3,4,5)P3 are concentrated in plasma membranes of eukaryotic cells, and excluded from endosomes, whereas PtdIns(3)P is formed in these latter intracellular membranes and is apparently excluded from the plasma membrane. The logic of this asymmetric disposition is now revealed by the nature of the effector proteins that selectively bind these lipids through specific modules and by the processes that they catalyze. PtdIns(3,4,5)P3 has a role in directing exocytosis, in addition to many other signaling events, whereas PtdIns(4,5)P2 directs endocytosis through its ability to anchor several coat proteins to the plasma membrane. Remarkably, the elimination of PtdIns(4,5)P2 from forming endosomes may be required for membrane fission to occur. Thus membrane insertion and retrieval can be regulated by plasma membrane concentrations of PtdIns(3,4,5)P3 and PtdIns(4,5)P2, whereas PtdIns(3)P directs the downstream trafficking and recycling of intracellular membranes through its attraction of proteins that catalyze these processes. The phosphoinositides thereby control many cell features that depend upon protein sorting, including the composition of the plasma membrane itself, which in turn determines the cell's responses to its environment.
Nuclear Receptors and the Control of Metabolism
Authors: Francis Gordon A. , Fayard Elisabeth , Picard Frédéric , Auwerx Johan
Published: January 2003

▪ Abstract  The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARγ); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARα, β/δ, and γ; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR). The transcriptional control of these metabolic circuits requires coordination between these metabolic receptors and other transcription factors and coregulators. Altered signaling by this subset of receptors, either through chronic ligand excess or genetic factors, may cause an imbalance in these homeostatic circuits and contribute to the pathogenesis of common metabolic diseases such as obesity, insulin resistance and type 2 diabetes, hyperlipidemia and atherosclerosis, and gallbladder disease. Further studies should exploit the fact that many of these nuclear receptors are designed to respond to small molecules and turn them into therapeutic targets for the treatment of these disorders.
Insulin Receptor Knockout Mice
Authors: Kitamura Tadahiro , Kahn C. Ronald , Accili Domenico
Published: January 2003

▪ Abstract  To examine the role of the insulin receptor in fuel homeostasis, we and others have carried out genetic ablation studies in mice. Mice lacking insulin receptors are born with normal features, but develop early postnatal diabetes and die of ketoacidosis. In contrast, mice lacking insulin receptors in specific cell types as a result of conditional mutagenesis develop mild metabolic and reproductive abnormalities. These experiments have uncovered novel functions of insulin receptors in tissues such as brain and pancreatic β-cells. Combined knockout studies of insulin and Igf1 receptors indicate that the insulin receptor also promotes embryonic growth. Experimental crosses of mice with insulin receptor haploinsufficiency have been instrumental to the genetic analysis of insulin action by enabling us to assign specific roles to different insulin receptor substrates and identify novel elements in insulin signaling.
Processive and Nonprocessive Models of Kinesin Movement
Authors: Endow Sharyn A. , Barker Douglas S.
Published: January 2003

▪ Abstract  Conventional kinesin is the prototypic member of a family of diverse proteins that use the chemical energy of ATP hydrolysis to generate force and move along microtubules. These proteins, which are involved in a wide range of cellular functions, have been identified in protozoa, fungi, plants, and animals and possess a high degree of sequence conservation among species in their motor domains. The biochemical properties of kinesin and its homologues, in conjunction with the recently solved three-dimensional structures of several kinesin motors, have contributed to our understanding of the mechanism of kinesin movement along microtubules. We discuss several models for movement, including the hand-over-hand, inchworm, and biased diffusion models of processive movement, as well as models of nonprocessive movement.
Structure and Mechanism of Na,K-ATPase: Functional Sites and Their Interactions
Authors: Jorgensen Peter L. , Håkansson Kjell O. , Karlish Steven J. D.
Published: January 2003

▪ Abstract  The cell membrane Na,K-ATPase is a member of the P-type family of active cation transport proteins. Recently the molecular structure of the related sarcoplasmic reticulum Ca-ATPase in an E1 conformation has been determined at 2.6 Å resolution. Furthermore, theoretical models of the Ca-ATPase in E2 conformations are available. As a result of these developments, these structural data have allowed construction of homology models that address the central questions of mechanism of active cation transport by all P-type cation pumps. This review relates recent evidence on functional sites of Na,K-ATPase for the substrate (ATP), the essential cofactor (Mg2+ ions), and the transported cations (Na+ and K+) to the molecular structure. The essential elements of the Ca-ATPase structure, including 10 transmembrane helices and well-defined N, P, and A cytoplasmic domains, are common to all PII-type pumps such as Na,K-ATPase and H,K-ATPases. However, for Na,K-ATPase and H,K-ATPase, which consist of both α- and β-subunits, there may be some detailed differences in regions of subunit interactions. Mutagenesis, proteolytic cleavage, and transition metal-catalyzed oxidative cleavages are providing much evidence about residues involved in binding of Na+, K+, ATP, and Mg2+ ions and changes accompanying E1-E2 or E1-P-E2-P conformational transitions. We discuss this evidence in relation to N, P, and A cytoplasmic domain interactions, and long-range interactions between the active site and the Na+ and K+ sites in the transmembrane segments, for the different steps of the catalytic cycle.
G Protein-Coupled Receptor Rhodopsin: A Prospectus
Authors: Filipek Sławomir , Stenkamp Ronald E. , Teller David C. , Palczewski Krzysztof
Published: January 2003

▪ Abstract  Rhodopsin is a retinal photoreceptor protein of bipartite structure consisting of the transmembrane protein opsin and a light-sensitive chromophore 11-cis-retinal, linked to opsin via a protonated Schiff base. Studies on rhodopsin have unveiled many structural and functional features that are common to a large and pharmacologically important group of proteins from the G protein-coupled receptor (GPCR) superfamily, of which rhodopsin is the best-studied member. In this work, we focus on structural features of rhodopsin as revealed by many biochemical and structural investigations. In particular, the high-resolution structure of bovine rhodopsin provides a template for understanding how GPCRs work. We describe the sensitivity and complexity of rhodopsin that lead to its important role in vision.
The Physiology of Cellular Liporegulation
Authors: Unger Roger H.
Published: January 2003

▪ Abstract  Here we explore the physiologic role of leptin as a liporegulatory hormone responsible for maintaining intracellular homeostasis in the face of wide variations in caloric intake. Normally, rats can tolerate a 60% fat diet because 96% of the surplus fat is deposited in adipocytes. In contrast, when leptin is congenitally absent or inactive, even on a normal diet, unutilized dietary fat is deposited in nonadipose tissues, causing dysfunction (lipotoxicity) and possible cell death (lipoapoptosis). We theorize that in diet-induced obesity, acquired leptin resistance may also develop as the result of increase in certain leptin resistance factors. Acquired leptin resistance occurs in aging, obesity, Cushing's syndrome, and acquired lipodystrophy, and preliminary evidence suggests that ectopic lipid deposition is increased. We speculate that the metabolic syndrome may be the human equivalent of the lipotoxic syndrome of rodents.
Mammalian Urea Transporters
Authors: Sands Jeff M.
Published: January 2003

▪ Abstract  Urea plays a key role in the urine-concentrating mechanism. Physiologic and molecular data demonstrate that urea transport in kidney and red blood cells occurs by specific urea transporter proteins. Two gene families for facilitated urea transporters, UT-A and UT-B, and several urea transporter cDNA isoforms have been cloned from human, rat, mouse, and several non-mammalian species. Polyclonal antibodies have been generated to many of the urea transporter proteins, and several novel findings have resulted from their use in integrative animal studies. For example, (a) vasopressin increases the phosphorylation of UT-A1 in rat inner medullary collecting duct; (b) UT-A1 protein abundance is increased in the rat inner medulla during conditions in which urine-concentrating ability is reduced; and (c) urea transporters are expressed in non-renal tissues, and UT-A protein abundance is up-regulated in uremia in both liver and heart. In addition to the facilitated urea transporters, functional evidence exists for active urea transport in the kidney collecting duct. This review summarizes the physiologic evidence for the existence of facilitated and active urea transporters, the molecular biology of the facilitated urea transporter gene families and cDNAs, and integrative studies into urea transporter protein regulation, both in the kidney and in other organs.
Terminal Differentiation of Intercalated Cells: The Role of Hensin
Authors: Al-Awqati Qais
Published: January 2003

▪ Abstract  During the response to metabolic acidosis, the intercalated cell of the collecting tubule converts from one that secretes HCO3− to one that absorbs HCO3− by H+ secretion. The molecular basis of this complex change in phenotype was studied in an immortalized intercalated cell line. We found that it was induced by secretion, polymerization, and deposition of a protein, which we termed hensin, into the extracellular matrix. Surprisingly, this change in phenotype is identical to terminal differentiation of epithelial cells in that it recapitulated all the characteristics of terminal differentiation, including a change in cell shape, acquisition of specialized apical structures (microvilli and ruffles), and the ability to secrete and endocytose materials in a regulated manner from the apical membrane. Hensin is expressed in most epithelia, and others have discovered that it is deleted in a large number of epithelial tumors. These results suggest that conversion of polarity of the intercalated cells represents a process of terminal differentiation.
Transducing Touch in Caenorhabditis elegans
Authors: Goodman Miriam B. , Schwarz Erich M.
Published: January 2003

▪ Abstract  Mechanosensation has been studied for decades, but understanding of its molecular mechanism is only now emerging from studies in Caenorhabditis elegans and Drosophila melanogaster. In both cases, the entry point proved to be genetic screens that allowed molecules needed for mechanosensation to be identified without any prior understanding of the likely components. In C. elegans, genetic screens revealed molecules needed for touch sensation along the body wall and other regions of force sensitivity. Members of two extensive membrane protein families have emerged as candidate sensory mechanotransduction channels: mec-4 and mec-10, which encode amiloride-sensitive channels (ASCs or DEG/ENaCs), and osm-9, which encodes a TRP ion channel. There are roughly 50 other members of these families whose functions in C. elegans are unknown. This article classifies these channels in C. elegans, with an emphasis on insights into their function derived from mutation. We also review the neuronal cell types in which these channels might be expressed and mediate mechanotransduction.
Origins and Consequences of Mitochondrial Variation in Vertebrate Muscle
Authors: Moyes Christopher D. , Hood David A.
Published: January 2003

▪ Abstract  This review addresses the mechanisms by which mitochondrial structure and function are regulated, with a focus on vertebrate muscle. We consider the adaptive remodeling that arises during physiological transitions such as differentiation, development, and contractile activity. Parallels are drawn between such phenotypic changes and the pattern of change arising over evolutionary time, as suggested by interspecies comparisons. We address the physiological and evolutionary relationships between ATP production, thermogenesis, and superoxide generation in the context of mitochondrial function. Our discussion of mitochondrial structure focuses on the regulation of membrane composition and maintenance of the three-dimensional reticulum. Current studies of mitochondrial biogenesis strive to integrate muscle functional parameters with signal transduction and molecular genetics, providing insight into the origins of variation arising between physiological states, fiber types, and species.
Functional Genomics and the Comparative Physiology of Hypoxia
Authors: Powell Frank L.
Published: January 2003

▪ Abstract  Comparative physiology has proven a powerful approach to our understanding of how animals function under hypoxic conditions and to identifying potential adaptations to environmental oxygen levels. This review considers the potential for using a similar comparative approach with functional genomics to understand the genetic basis of such physiological processes and evolutionary adaptations. Comparative functional genomics is currently limited by genome data, which are available for only a few model organisms. However, comparative studies between model organisms of the same species having slightly different genomes (e.g., in-bred strains of laboratory rodents, transgenic mice, and consomic rats) demonstrate the types of results, as well as the analytical challenges, that are possible if comparative functional genomics is applied to more species. Results from wild and domestic animal studies suggest new models to investigate physiological and evolutionary responses to oxygen levels with functional genomics.
Application of Microarray Technology in Environmental and Comparative Physiology
Authors: Gracey Andrew Y. , Cossins Andrew R.
Published: January 2003

▪ Abstract  DNA microarray technology is revolutionizing many aspects of biological research, allowing the expression of many thousands of gene transcripts to be monitored simultaneously. This provides powerful tools for the genome-wide correlation of gene transcript levels with physiological responses and alterations in physiological states. To date, microarray analyses have been applied almost exclusively to a few model species for which the abundant gene sequence data permit the fabrication of whole-genome microarrays. However, many interesting physiological traits and responses are poorly expressed or absent in model species and may be better illustrated in nonmodel organisms. Comparative approaches to understanding function traditionally focus on species that by virtue of their unusual adaptations, lifestyles, and phylogeny are particularly suited to address a specific biological process or problem. In this review, we show that microarray technology can be successfully applied to these nonmodel species and used to generate new insights of comparative and evolutionary significance into animal function.
Hyperpolarization-Activated Cation Currents: From Molecules to Physiological Function
Authors: Robinson Richard B. , Siegelbaum Steven A.
Published: January 2003

▪ Abstract  Hyperpolarization-activated cation currents, termed If, Ih, or Iq, were initially discovered in heart and nerve cells over 20 years ago. These currents contribute to a wide range of physiological functions, including cardiac and neuronal pacemaker activity, the setting of resting potentials, input conductance and length constants, and dendritic integration. The hyperpolarization-activated, cation nonselective (HCN) gene family encodes the channels that underlie Ih. Here we review the relation between the biophysical properties of recombinant HCN channels and the pattern of HCN mRNA expression with the properties of native Ih in neurons and cardiac muscle. Moreover, we consider selected examples of the expanding physiological functions of Ih with a view toward understanding how the properties of HCN channels contribute to these diverse functional roles.
Acetylsalicylic Acid Inhibits Cell Proliferation by Involving Transforming Growth Factor-β
Authors: Redondo Santiago , Santos-Gallego Carlos G. , Ganado Patricia , García Marta , Rico Laura , Del Rio Marcela , Tejerina Teresa
Published: February 2003

Background—

Acetylsalicylic acid (ASA) inhibits cell proliferation. This may be mediated by transforming growth factor-β (TGF-β). TGF-β directly stops cell proliferation, restrains cells in G
0
, and inhibits the uptake of platelet-derived growth factor and insulin-like growth factor. These effects are identical to those observed with ASA treatment.

Methods and Results—

We cultured rat thoracic aorta vascular smooth muscle cells and measured cytotoxicity, cell proliferation, cell cycle, transcription of TGF-β
1
, and concentration of TGF-β
1
in supernatant medium. ASA dose-dependently restrained cells in G
0
phase with no cytotoxic effect and inhibited cell proliferation by 30.86%. Anti–TGF-β
1
reversed this inhibition by 30.21%. However, ASA treatment decreased TGF-β
1
transcription and had no significant effect on TGF-β
1
concentration.

Conclusions—

TGF-β seems to play an important role in ASA-mediated inhibition of cell proliferation. Therefore, treatment with ASA prevents coronary disease not only by means of its antiplatelet properties but also by an important inhibition of plaque growth. This relationship between ASA and TGF-β explains many other effects, such as cancer chemoprevention, immunomodulation, and wound healing. The aim of this study was to demonstrate this link.
Combination of a Normal D-Dimer Concentration and a Non-High Pretest Clinical Probability Score Is a Safe Strategy to Exclude Deep Venous Thrombosis
Authors: Schutgens R.E.G. , Ackermark P. , Haas F.J.L.M. , Nieuwenhuis H.K. , Peltenburg H.G. , Pijlman A.H. , Pruijm M. , Oltmans R. , Kelder J.C. , Biesma D.H.
Published: February 2003

Background—

Serial ultrasonography is reliable for the diagnosis of deep venous thrombosis in symptomatic patients, but the low prevalence of thrombosis in this group renders the approach costly and inconvenient to patients. We studied the clinical validity of the combination of a pretest clinical probability score and a D-dimer test in the initial evaluation of patients suspected of deep venous thrombosis.

Methods and Results—

Patients with a normal D-dimer concentration (<500 fibrin equivalent units [FEU] μg/L) and a non-high probability score (<3) had no further testing. Patients with a normal D-dimer concentration and a high probability score (≥3) underwent one ultrasonogram. Serial ultrasonography was performed in patients with an abnormal D-dimer concentration. Patients were followed for 3 months. A total of 812 patients were evaluable for efficacy. Only 1 of 176 patients (0.6%; 95% CI, 0.02% to 3.1%) with a normal D-dimer concentration and a non-high probability score developed thrombosis during follow-up. A normal D-dimer concentration and a high probability score were found in 39 patients; 3 of them (7.7%; 95% CI, 1.6% to 20.9%) had thrombosis at presentation, and one (2.8%; 95% CI, 0.07% to 14. 5%) developed pulmonary embolism during follow-up. In 306 of 597 patients (51.3%) with an abnormal D-dimer concentration, thrombosis was detected by serial ultrasonography. Six patients (2.1%; 95% CI, 0.8% to 4. 4%) developed thrombosis during follow-up. No deaths due to thromboembolism occurred during follow-up. The total need for ultrasonography was reduced by 29%.

Conclusion—

The combination of a non-high pretest clinical probability score and a normal D-dimer concentration is a safe strategy to rule out deep venous thrombosis and to withhold anticoagulation.
Altered Myocardial Thin-Filament Function in the Failing Dahl Salt-Sensitive Rat Heart
Authors: Noguchi Teruo , Kihara Yasuki , Begin Kelly J. , Gorga Joseph A. , Palmiter Kimberly A. , LeWinter Martin M. , VanBuren Peter
Published: February 2003

Background—

Dahl salt-sensitive rats fed a high-salt diet develop compensated left ventricular hypertrophy followed by a transition to myocardial failure. We previously reported an increase in a troponin T isoform (TnT
3
) and a decrease in TnT phosphorylation in failing Dahl salt-sensitive rat hearts compared with low-salt controls. The present study was undertaken to determine whether the thin filament plays a role in depression of the contractile machinery in this model.

Methods and Results—

Native thin filaments (NTFs) were isolated intact from rats with compensated left ventricular hypertrophy and failing hearts and compared with age-matched controls. NTF velocity was measured as a function of free calcium in the in vitro motility assay. Maximal velocity was similar in all groups. However, NTFs from failing hearts demonstrated a reduction in calcium sensitivity compared with controls, as reflected in the pCa
50
(5.88±0.05 versus 6.22±0.05, respectively,
P
<0.001). No difference in thin-filament motility (pCa
50
, V
max
) was observed in rats with compensated left ventricular hypertrophy compared with controls. Protein kinase A treatment of NTFs from control and failing hearts had no effect on thin-filament calcium sensitivity. However, the endothelin receptor blocker bosentan prevented the reduction in thin-filament calcium sensitivity found in failing hearts.

Conclusions—

The thin filament is a key modulator of contractile performance in the transition to failure in the Dahl salt-sensitive rat model. The alteration in thin-filament function may be mediated by an endothelin-triggered pathway potentially affecting protein kinase C signaling.
Angiotensin-Converting Enzyme Inhibition Increases Human Vascular Tissue-Type Plasminogen Activator Release Through Endogenous Bradykinin
Authors: Pretorius Mias , Rosenbaum David , Vaughan Douglas E. , Brown Nancy J.
Published: February 2003

Background—

Angiotensin-converting enzyme (ACE) inhibition potentiates the tissue-type plasminogen activator (t-PA) response to exogenous bradykinin. This study tested the hypothesis that ACE inhibition increases endothelial t-PA release through endogenous bradykinin.

Methods and Results—

We measured the effect of intra-arterial enalaprilat (5 μg/min) on forearm blood flow (FBF) and net t-PA release before and during intra-arterial infusion of bradykinin (25 to 400 ng/min) and methacholine (3.2 to 12.8 μg/min) in 24 smokers pretreated with bradykinin receptor antagonist HOE 140 (100 μg/kg intravenously) or vehicle. There was no specific effect of HOE 140 on FBF or forearm vascular resistance (FVR, 29.9±3.6 versus 29.7±3.6 mm Hg · mL
−1
· min
−1
· 100 mL
−1
after vehicle and HOE 140, respectively,
P
=0.956 between groups). Resting FVR decreased during enalaprilat compared with vehicle or HOE 140, but not compared with baseline, and the effect was similar in the 2 groups (22.0±2.7 and 24.1±2.9 mm Hg · mL
−1
· min
−1
· 100 mL
−1
, respectively,
P
=0.610). In contrast, enalaprilat significantly increased resting net t-PA release (from 0.6±0.4 to 1.7±0.6 ng · min
−1
· 100 mL
−1
,
P
=0.002); this effect was abolished by HOE 140 (0.1±0.3 ng · min
−1
· 100 mL
−1
,
P
=0.036 versus enalaprilat alone). Enalaprilat increased the effect of exogenous bradykinin on FBF 60% (from 17.5±2.5 to 28.1±4.0 mL · min
−1
· 100 mL
−1
during 100 ng/min bradykinin,
P
=0.001) and on t-PA release 14-fold (from 21.2±7.9 to 317.4±118.9 ng · min
−1
· 100 mL
−1
,
P
=0.024). Enalaprilat increased the t-PA response to bradykinin to a greater extent than the FBF response, shifting the relationship between net t-PA release and FBF (
P
=0.005). HOE 140 blocked these effects. There was no effect of enalaprilat or HOE 140 on the FBF or t-PA response to methacholine.

Conclusion—

ACE inhibition increases constitutive endothelial t-PA release through endogenous bradykinin.
Differential Regulation of Natriuresis by 20-Hydroxyeicosatetraenoic Acid in Human Salt-Sensitive Versus Salt-Resistant Hypertension
Authors: Laffer Cheryl L. , Laniado-Schwartzman Michal , Wang Mong-Heng , Nasjletti Alberto , Elijovich Fernando
Published: February 2003

Background—

Twenty-hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450 metabolite of arachidonic acid that produces vasoconstriction and inhibition of renal tubular sodium transport. In Dahl rats, a 20-HETE deficiency plays a role in salt-sensitive (SS) hypertension. In humans, there are no data on regulation of 20-HETE by salt intake or on a role for this compound in SS hypertension.

Methods and Results—

Thirteen salt-resistant (SR) and 13 SS hypertensive subjects had urine 20-HETE excretion measured during salt-loading and depletion. In all patients, 20-HETE was 66.6% higher in the salt-replete (1.75±0.25 μg/h) than in the salt-depleted state (1.05±0.16,
P
<0.003). There was no difference in 20-HETE excretion between SR and SS patients in either state of salt balance. In SR patients, sodium excretion during salt-loading correlated with 20-HETE (
r
=0.61,
P
<0.03) but not with blood pressure. In contrast, in SS patients, sodium excretion did not correlate with 20-HETE but did correlate with blood pressure (
r
=0.66,
P
<0.02). Finally, in the SS group only, there was a negative correlation between body mass index and 20-HETE excretion (
r
=−0.79,
P
<0.002) that was present during both salt-loading and depletion.

Conclusions—

We demonstrate for the first time that 20-HETE excretion is regulated by salt intake in hypertension. We find a disrupted relationship between sodium excretion and 20-HETE in SS patients, which results in dependence of their salt excretion on blood pressure and may be related to the magnitude of their obesity. We conclude that salt-sensitivity of blood pressure in essential hypertension may result from impairment of a natriuretic mechanism dependent on 20-HETE.
Myocardial Infarct Expansion and Matrix Metalloproteinase Inhibition
Authors: Mukherjee Rupak , Brinsa Theresa A. , Dowdy Kathryn B. , Scott Amelia A. , Baskin Julia M. , Deschamps Anne M. , Lowry Abigail S. , Escobar G. Patricia , Lucas David G. , Yarbrough William M. , Zile Michael R. , Spinale Francis G.
Published: February 2003

Background—

A potential mechanism for left ventricular (LV) remodeling after myocardial infarction (MI) is activation of the matrix metalloproteinases (MMPs). This study examined the effects of MMP inhibition (MMPi) on regional LV geometry and MMP levels after MI.

Methods and Results—

In pigs instrumented with radiopaque markers to measure regional myocardial geometry, MI was created by ligating the obtuse marginals of the circumflex artery. In the first study, pigs were randomized to MMPi (n=7; PD166793, 20 mg · kg
−1
· d
−1
) or MI only (n=7) at 5 days after MI, and measurements were performed at 2 weeks. Regional MI areas were equivalent at randomization and were increased in the MI-only group at 2 weeks after MI compared with the MMPi group. In the second study, pigs randomized to MMPi (n=9) or MI only (n=8) were serially followed up for 8 weeks. At 8 weeks after MI, LV end-diastolic dimension was lower with MMPi than in the MI-only group (4.7±0.1 versus 5.1±0.1 cm,
P
<0.05). Regional MI area was reduced with MMPi at 8 weeks after MI (1.3±0.1 versus 1.7±0.1 cm
2
,
P
<0.05). MMPi reduced ex vivo MMP proteolytic activity. In the MI region, membrane-type MMP levels were normalized and levels of the endogenous tissue inhibitor of MMPs (TIMP-1) were increased compared with normal levels with MMPi. These effects were not observed in the MI-only group.

Conclusions—

MMPi attenuated the degree of post-MI LV dilation and expansion of the infarct during the late phase of MI healing. In addition, exogenous MMPi caused region-specific modulation of certain MMP and TIMP species.
Matrix Metalloproteinase-9 Pretreatment Level Predicts Intracranial Hemorrhagic Complications After Thrombolysis in Human Stroke
Authors: Montaner Joan , Molina Carlos A. , Monasterio Jasone , Abilleira Sonia , Arenillas Juan F. , Ribó Marc , Quintana Manolo , Alvarez-Sabín José
Published: February 2003

Background—

Matrix metalloproteinase (MMP) expression is related to blood brain barrier disruption after cerebral ischemia. Moreover, MMP inhibitors reduce hemorrhagic transformation (HT) after embolic ischemia in tissue plasminogen activator (t-PA)–treated animals. We aimed to correlate plasmatic MMP levels with the appearance of intracranial bleeding complications in stroke patients treated with t-PA.

Methods and Results—

Serial MMP-2 and MMP-9 determinations were performed (ELISA, ng/mL) in 41 strokes involving the middle cerebral artery territory in patients who received t-PA within 3 hours of stroke onset. Blood samples were obtained at baseline (pretreatment) and at 12 and 24 hours after symptom onset. Hemorrhagic events were classified according to CT criteria (petechial hemorrhagic infarctions [HI, 1 to 2] and large parenchymal hemorrhages [PH, 1 to 2]). Brain CT scan was obtained at 48 hours or when a neurological worsening occurred. HT was present in 36.5% of the patients (24.4% HI and 12.1% PH). MMP-2 values were unrelated to any subtype of HT. The highest baseline MMP-9 level (normal range <97 ng/mL) corresponded to patients who later developed a PH (PH: 270.2±87.8, non-HT: 126.3±127.5, HI: 94.6±88.7;
P
=0.047). A graded response was found between mean baseline MMP-9 levels and the degree of bleeding (HI-1=37.4; HI-2=111.0; PH-1=202.5; PH-2=337.8). Baseline MMP-9 was the most powerful predictor of PH appearance in the multiple logistic regression model (OR= 9.62; CI 1.31 to 70.26;
P
=0.025).

Conclusions—

Baseline MMP-9 level predicts PH appearance after t-PA treatment. Therefore, we suggest that MMP determination may increase the safety profile for thrombolysis and, in the future, anti-MMP drugs might be combined with t-PA to prevent hemorrhagic complications.
Identification of Hibernating Myocardium With Quantitative Intravenous Myocardial Contrast Echocardiography
Authors: Shimoni Sarah , Frangogiannis Nikolaos G. , Aggeli Constadina J. , Shan Kesavan , Verani Mario S. , Quinones Miguel A. , Espada Rafael , Letsou George V. , Lawrie Gerald M. , Winters William L. , Reardon Michael J. , Zoghbi William A.
Published: February 2003

Background—

There are currently no data on the accuracy of intravenous myocardial contrast echocardiography (MCE) in detecting myocardial hibernation in man and its comparative accuracy to dobutamine echocardiography (DE) or thallium 201 (Tl
201
) scintigraphy.

Methods and Results—

Twenty patients with coronary artery disease and ventricular dysfunction underwent MCE 1 to 5 days before bypass surgery and repeat echocardiography at 3 to 4 months. Patients also underwent DE (n=18) and rest-redistribution Tl
201
tomography (n=16) before revascularization. MCE was performed using continuous Optison infusion (12 to 16 cc/h) with intermittent pulse inversion harmonics and incremental triggering (1:1 to 1:8). Myocardial contrast intensity (MCI) replenishment curves were constructed to derive quantitative MCE indices of blood velocity and flow. Recovery of function occurred in 38% of dysfunctional segments. MCE parameters of perfusion in hibernating myocardium were similar to segments with normal function and higher than dysfunctional myocardium without recovery of function (
P
<0.001). The best MCE parameter for predicting functional recovery was Peak MCI×β, an index of myocardial blood flow (area under the curve, 0.83). MCE parameters were higher in segments with contractile reserve and Tl
201
uptake ≥60% (
P
<0.05) and identified viable segments without contractile reserve by DE. The sensitivity of Peak MCI×β >1.5 dB/s for recovery of function was 90% and was similar to Tl
201
scintigraphy (92%) and any contractile reserve (80%); specificity was higher than for Tl
201
and DE (63%, 45%, and 54%, respectively;
P
<0.05).

Conclusions—

MCE with intravenous contrast identifies myocardial hibernation in humans. Prediction of viable myocardium with MCE is best using quantification of myocardial blood flow and provides improved accuracy compared with DE and Tl
201
scintigraphy.
Intravascular Ultrasound–Guided Balloon Angioplasty Compared With Stent
Authors: Schiele François , Meneveau Nicolas , Gilard Martine , Boschat Jacques , Commeau Philippe , Ming Liu Pin , Sewoke Pradip , Seronde Marie-France , Mercier Mariette , Gupta Sanjiv , Bassand Jean-Pierre
Published: February 2003

Background—

Balloon angioplasty guided by intravascular ultrasound (IVUS) makes it possible to choose the balloon size according to the true vessel diameter and to detect suboptimal results requiring subsequent stent implantation. The Balloon Equivalent to STent (BEST) study aimed to assess whether this strategy would give the same results as systematic stenting.

Methods and Results—

A total of 132 of 254 patients were randomized to IVUS-guided percutaneous transluminal coronary angioplasty (aggressive PTCA), and 122 were randomized to stenting (stent group). We hypothesized that a difference of <8% in the 6-month angiographic restenosis rate (primary end point) could be considered noninferior. The aggressive PTCA procedure was longer and had a greater use of contrast medium than stenting. In the aggressive PTCA group, crossover to stent was needed in 58 patients (44%). At 6 months, 20 of 119 patients (16.8±6.7%) in the aggressive PTCA group and 21 of 116 patients (18.1±7.0%) in the stent group had restenosis. The difference was −1.3%, with an upper limit of 95% confidence interval of 7.1% (ie, less than the noninferiority boundary). The in-stent restenosis rate was higher in the stent group (15.5% versus 5%;
P
=0.02). The differences in minimum lumen diameter, lumen cross-section area, and 1-year event rate were not significant.

Conclusions—

A strategy of IVUS-guided angioplasty with provisional stenting is feasible and safe. At the cost of a more complex procedure, it reduces the stent rate by half, with similar 6-month angiographic IVUS and clinical outcome compared with stent implantation.
Short-Term Heart Rate Variability Strongly Predicts Sudden Cardiac Death in Chronic Heart Failure Patients
Authors: La Rovere Maria Teresa , Pinna Gian Domenico , Maestri Roberto , Mortara Andrea , Capomolla Soccorso , Febo Oreste , Ferrari Roberto , Franchini Mariella , Gnemmi Marco , Opasich Cristina , Riccardi Pier Giorgio , Traversi Egidio , Cobelli Franco
Published: February 2003

Background—

The predictive value of heart rate variability (HRV) in chronic heart failure (CHF) has never been tested in a comprehensive multivariate model using short-term laboratory recordings designed to avoid the confounding effects of respiration and behavioral factors.

Methods and Results—

A multivariate survival model for the identification of sudden (presumably arrhythmic) death was developed with data from 202 consecutive patients referred between 1991 and 1995 with moderate to severe CHF (age 52±9 years, left ventricular ejection fraction 24±7%, New York Heart Association class 2.3±0.7; the derivation sample). Time- and frequency-domain HRV parameters obtained from an 8′ recording of ECG at baseline and during controlled breathing (12 to 15 breaths/min) were challenged against clinical and functional parameters. This model was then validated in 242 consecutive patients referred between 1996 and 2001 (validation sample). In the derivation sample, sudden death was independently predicted by a model that included low-frequency power (LFP) of HRV during controlled breathing ≤13 ms
2
and left ventricular end-diastolic diameter ≥77 mm (relative risk [RR] 3.7, 95% CI 1.5 to 9.3, and RR 2.6, 95% CI 1.0 to 6.3, respectively). The derivation model was also a significant predictor in the validation sample (
P
=0.04). In the validation sample, LFP ≤11 ms
2
during controlled breathing and ≥83 ventricular premature contractions per hour on Holter monitoring were both independent predictors of sudden death (RR 3.0, 95% CI 1.2 to 7.6, and RR 3.7, 95% CI 1.5 to 9.0, respectively).

Conclusions—

Reduced short-term LFP during controlled breathing is a powerful predictor of sudden death in patients with CHF that is independent of many other variables. These results refine the identification of patients who may benefit from prophylactic implantation of a cardiac defibrillator.
LOX-1 Mediates Oxidized Low-Density Lipoprotein-Induced Expression of Matrix Metalloproteinases in Human Coronary Artery Endothelial Cells
Authors: Li Dayuan , Liu Ling , Chen Hongjiang , Sawamura Tatsuya , Ranganathan Subramanian , Mehta Jawahar L.
Published: February 2003

Background—

Oxidized LDL (ox-LDL) accumulation in the atherosclerotic region may enhance plaque instability. Both accumulation of ox-LDL and expression of its lectin-like receptor, LOX-1, have been shown in atherosclerotic regions. This study was designed to examine the role of LOX-1 in the modulation of metalloproteinases (MMP-1 and MMP-3) in human coronary artery endothelial cells (HCAECs).

Methods and Results—

HCAECs were incubated with ox-LDL (10 to 80 μg/mL) for 1 to 24 hours. Ox-LDL increased the expression of MMP-1 (collagenase) and MMP-3 (stromelysin-1) in a concentration- and time-dependent manner. Ox-LDL also increased collagenase activity. Ox-LDL did not significantly affect the expression of tissue inhibitors of metalloproteinases. Native LDL had no effect on the expression of MMPs. The effects of ox-LDL were mediated by its endothelial receptor, LOX-1, because pretreatment of HCAECs with a blocking antibody to LOX-1 (JTX92, 10 μg/mL) prevented the expression of MMPs in response to ox-LDL (
P
<0.01). In parallel experiments, ox-LDL caused the activation of protein kinase C (PKC), which was inhibited by LOX-1 antibody. The PKC-β isoform played a critical role in the expression of MMPs, because the PKC-β inhibitor hispidin reduced ox-LDL-induced activation of PKC and the expression of MMPs. Other PKC subunits (α, γ, and ε) did not affect the expression of MMPs.

Conclusions—

These findings indicate that ox-LDL, via LOX-1 activation, modulates the expression and activity of MMPs in HCAECs. In this process, activation of the PKC-β subunit plays an important signaling role.
Nicotine Strongly Activates Dendritic Cell–Mediated Adaptive Immunity
Authors: Aicher Alexandra , Heeschen Christopher , Mohaupt Mariette , Cooke John P. , Zeiher Andreas M. , Dimmeler Stefanie
Published: February 2003

Background—

Antigen-presenting cells (APCs) such as monocytes and dendritic cells (DCs) stimulate T-cell proliferation and activation in the course of adaptive immunity. This cellular interaction plays a role in the growth of atherosclerotic plaques. Nicotine has been shown to increase the growth of atherosclerotic lesions. Therefore, we investigated whether nicotine can stimulate APCs and their T cell–stimulatory capacity using human monocyte–derived DCs and murine bone marrow–derived DCs as APCs.

Methods and Results—

Nicotine dose-dependently (10
−8
to 10
−4
mol/L) induced DC expression of costimulatory molecules (ie, CD86, CD40), MHC class II, and adhesion molecules (ie, LFA-1, CD54). Moreover, nicotine induced a 7.0-fold increase in secretion of the proinflammatory T
H
1 cytokine interleukin-12 by human DCs. These effects were abrogated by the nicotinic receptor antagonist α-bungarotoxin and mecamylamine, respectively. The effects of nicotine were mediated in part by the phosphorylation of the PI3 kinase downstream target Akt and the mitogen-activated kinases ERK and p38 MAPK. Nicotine-stimulated APCs had a greater capacity to stimulate T-cell proliferation and cytokine secretion, as documented by mixed lymphocyte reactions and ovalbumin-specific assays with ovalbumin-transgenic DO10.11 mice. In a murine model of atherosclerosis, nicotine significantly enhanced the recruitment of DCs to atherosclerotic lesions in vivo.

Conclusions—

Nicotine activates DCs and augments their capacity to stimulate T-cell proliferation and cytokine secretion. These effects of nicotine may contribute to its influence on the progression of atherosclerotic lesions.
Myocardial Production of C-Type Natriuretic Peptide in Chronic Heart Failure
Authors: Kalra Paul R. , Clague Jonathon R. , Bolger Aidan P. , Anker Stefan D. , Poole-Wilson Phillip A. , Struthers Allan D. , Coats Andrew J.
Published: February 2003

Background—

C-type natriuretic peptide (CNP) is a vasodilator produced by the vascular endothelium. It shares structural and physiological properties with the cardiac hormones atrial natriuretic peptide and brain natriuretic peptide (BNP), but little is known about its pathophysiological role in chronic heart failure (CHF). We assessed the hypothesis that CNP is produced by the heart in patients with CHF.

Methods and Results—

Myocardial CNP production was determined (difference in plasma levels between the aortic root and coronary sinus [CS]) in 9 patients undergoing right and left heart catheterization as part of their CHF assessment (all male, age 59±9 years; New York Heart Association class 2.2±0.1; left ventricular ejection fraction 29±5%; creatinine 105±8 μmol/L [all values mean±SEM]). BNP, established as originating from myocardium, was assessed from the same samples as a positive control. Analyses were performed by a blinded operator using a standard competitive radioimmunoassay kit (Peninsula Laboratories, Bachem Ltd UK). A step-up (29%) in plasma CNP concentration was found from the aorta to the CS (3.55±1.53 versus 4.59±1.54 pg/mL, respectively;
P
=0.035). The mean increase in CNP was 0.90±0.35 pg/mL (range 0.05 to 2.80 pg/mL). BNP levels increased by 57% from aorta to CS (86.0±20.5 versus 135.0±42.2 pg/mL;
P
=0.01). CS CNP levels correlated with mean pulmonary capillary wedge pressure (
r
=0.82,
P
=0.007).

Conclusions—

We have shown that CNP is produced by the heart in patients with CHF. Although further evaluation is required to define its full pathophysiological role in this condition, CNP may represent an important new local mediator in the heart.
Effects of AGI-1067 and Probucol After Percutaneous Coronary Interventions
Authors: Tardif Jean-Claude , Grégoire Jean , Schwartz Leonard , Title Lawrence , Laramée Louise , Reeves François , Lespérance Jacques , Bourassa Martial G. , L’Allier Philippe L. , Glass Mitchell , Lambert Jean , Guertin Marie-Claude
Published: February 2003

Background—

AGI-1067, a metabolically stable modification of probucol, is an equipotent antioxidant to probucol but is pharmacologically distinct. In a multicenter trial, we studied whether AGI-1067 reduces restenosis assessed by intravascular ultrasound (IVUS) after percutaneous coronary intervention (PCI) compared with placebo and probucol used as a positive control.

Methods and Results—

Two weeks before PCI, 305 patients were randomly assigned to 1 of 5 treatment groups: placebo, probucol 500 mg BID, or AGI-1067 70, 140, or 280 mg once daily. Patients were treated for 2 weeks before and 4 weeks after PCI. Baseline and 6-month follow-up IVUS were interpreted by a blinded core laboratory. Stents were used in 85% of patients. Luminal area at the PCI site at follow-up was 2.66±1.58 mm
2
for placebo, 3.69±2.69 mm
2
for probucol, 2.75±1.76 mm
2
for AGI-1067 70 mg, 3.17±2.26 mm
2
for AGI-1067 140 mg, and 3.36±2.12 mm
2
for AGI-1067 280 mg (
P
=0.02 for the dose-response relationship;
P
≤0.05 for AGI-1067 280 mg and probucol versus placebo). There was a mean narrowing of 5.3 mm
3
of reference segment lumen in the placebo group and an enlargement in the AGI-1067 140- and 280-mg groups at follow-up (
P
=0.05 for 140 mg). An increase in QTc interval >60 ms occurred in 4.8% of placebo patients, 17.4% of probucol patients, and 4.8%, 2.4%, and 2.5% of patients in the AGI-1067 groups (
P
=0.02).

Conclusions—

AGI-1067 and probucol reduce restenosis after PCI. In contrast to probucol, AGI-1067 did not cause prolongation of the QTc interval and improved lumen dimensions of reference segments, suggestive of a direct effect on atherosclerosis.