HAART and Heart Disease
The use of combinations of antiretroviral drugs including nucleoside analogs, protease inhibitors (PIs) and reverse transcriptase inhibitors - collectively termed highly active anti-retroviral therapy (HAART) - has resulted in a dramatic improvement in health status for a large number of HIV-infected individuals.
Side effects in many users, however, cause non-adherence to treatment regimes and concern over their long-term use in the management of chronic HIV infection. The adverse effects of PIs include abnormalities in lipid metabolism, insulin resistance, and premature atherosclerosis. Whether the latter is caused directly by the drugs or as a consequence of lipid abnormalities and insulin resistance has not been clear, until now.
A report in the February 3 issue of the Journal of Clinical Investigation shows that HIV protease inhibitors directly promote atherosclerosis in mice. Led by Eric Smart, the researchers from the University of Kentucky Medical School in Lexington also examined the situation in human cells, and found that protease inhibitors induced changes in particular cells (called macrophages) that are like those seen in atherosclerotic lesions.
In an accompanying Commentary article, David Hui, a heart disease specialist at the University of Cincinnati College of Medicine, discusses the implications of these findings. He proposes a mechanism by which these drugs might promote heart disease, and suggests ways to disrupt it.
CONTACT:
Eric Smart
University of Kentucky
Department of Physiology
423 Sanders-Brown
800 South Limestone
Lexington, KY 40536
USA
Phone 1: 859-323-6412
Fax 1: 859-323-1070
E-mail: ejsmart@uky.edu
View the PDF of this article at: https://www.the-jci.org/press/16261.pdf
ACCOMPANYING COMMENTARY:
HIV Protease Inhibitors and Atherosclerosis
CONTACT:
David Y. Hui
University Of Cincinnati College Of Med.
Department Of Pathology and Laboratory Medicine
231 Albert Sabin Way
Mail Stop 529
Cincinnati, OH 45267-0529
USA
Phone 1: 513-558-9152
Fax 1: 513-558-2141
E-mail: huidy@email.uc.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17746.pdf
Artemis: a little bit is not enough
Two years ago, when studying children with severe combined immune deficiency and reduced tolerance to radiation, Jean-Pierre de Villartay and colleagues of the Hopital Necker Enfants-Malades in Paris found that the disease was caused by mutations in a particular gene. They called the gene Artemis, after the Greek patroness of children and animals. Subsequent studies showed that the gene's protein product is involved in the repair of broken DNA, therefore explaining the children's illness: the generation of the vast repertoire of immune cells (B and T cells) that protect us against pathogens involves the breakage and rejoining of DNA. Exposure to radiation also results in DNA breaks that can, to some extent, be repaired by a functioning DNA repair system.
The children from the previous study had no functional Artemis protein, which resulted in severe problems with their DNA repair system. De Villartay and co-workers now report in the February 3 issue of the Journal of Clinical Investigation that individuals who have reduced levels of functional Artemis protein (caused by so-called hypomorphic mutations in the Artemis gene) suffer from a milder form of immunodeficiency and appear prone to develop lymphomas - malignant disease that originates in B or T cells.
These findings suggest that mutations in Artemis or other DNA repair genes could be responsible for other cases of immune deficiency and/or lymphoma. In an accompanying Commentary, Vicky Brandt and David Roth (of The Skirball Institute of Biomolecular Medicine at New York University Medical School) discuss the article in the context of our knowledge of DNA repair and its role in immune cell development and as a guardian against cancer.
CONTACT:
Jean-Pierre de Villartay
INSERM U429
Hopital Necker Enfants-Malades
149 rue de Sevres
75015 Paris
FRANCE
PHONE: 33-1-44-49-50-81
FAX: 33-1-42-73-06-40
E-mail: DEVILLAR@INFOBIOGEN.FR
View the PDF of this article at: https://www.the-jci.org/press/16774.pdf
ACCOMPANYING COMMENTARY:
Artemis: guarding small children and, now, the genome
CONTACT:
David Roth
Skirball Institute of Biomolecular Medicine
NYU School of Medicine
540 First Avenue
New York, NY 10016
USA
PHONE: 212-263-0945
E-mail: roth@saturn.med.nyu.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17743.pdf
ONLINE FIRST ARTICLES
Decreased atherosclerosis in CX3CR1–/– mice reveals a role for fractalkine in atherogenesis
CONTACT:
Israel F. Charo
Gladstone Institutes of Cardiovascular Disease
P.O. Box 419100
San Francisco, CA 94141-9100
USA
Phone 1: 415-826-7500
Fax 1: 415-285-5632
E-mail: icharo@gladstone.ucsf.edu
View the PDF of this article at: https://www.the-jci.org/press/15555.pdf
TABLE OF CONTENTS
No obesity without UCP1
Energy expenditure through brown adipose tissue (BAT) thermogenesis contributes to the maintenance of body temperature in a cold environment and to the burning of excess food energy. It depends on uncoupling protein 1(UCP1) which uncouples respiration from ATP synthesis in the mitochondria of brown adipocytes. Studying UCP1 function in mice, Leslie Kozak and colleagues have constructed congenic lines that lack UCP1 on different genetic backgrounds. On pages 399-407 they confirm previous unexpected findings--complicated by a mixed genetic background – that UCP1 mutants are resistant to diet-induced obesity, and proposed that in the absence of BAT non-shivering thermogenesis the animals are forced to employ alternative thermogenic mechanisms that are metabolically more expensive. These alternative mechanisms, which remain to be identified, could also influence metabolism and body weight in adult humans who are largely devoid of BAT and UCP1.
CONTACT:
Leslie Kozak
Penningtion Biomedical Research Ctr.
Louisiana State University
6400 Perkins Rd.
Baton Rouge, LA 70808-4124
USA
Phone 1: 225-763-2771
Fax 1: 225-763-3030
E-mail: kozaklp@pbrc.edu
View the PDF of this article at: https://www.the-jci.org/press/15737.pdf
LpL location and lipid uptake in the heart
Cardiomyocytes express lipoprotein lipase (LpL) that dissociates from the cell surface and migrates to the luminal surface of capillary endothelial cells, where it interacts with lipid particles and converts triglycerides to free fatty acids. The latter then cross the endothelial barrier and are taken up by cardiomyocytes and used to generate energy. Ira Goldberg and colleagues have tethered LpL to the cardiomyocyte surface to test whether the enzyme is only active after its translocation. As they report (pages 419-426), LpL anchored to the cardiomyocyte surface also promotes lipid uptake. In fact, mice carrying the transgene exhibited increased lipid accumulation and dilated cardiomyopathy. The authors conclude that some lipid particles must be able to enter the subendothelial space and directly interact with cardiomyocytes, and that this may play a role in normal physiology as well.
CONTACT:
Ira J. Goldberg
Columbia University
Division of Preventive Medicine and Nutrition
630 West 168th Street
New York, NY 10032
USA
Phone 1: 212-305-3678
Fax 1: 212-305-5384
E-mail: ijg3@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/16751.pdf
Nucleotides and electrotransport in the colon
Members of the P2Y family of G protein--–coupled receptors regulate ion transport in epithelial cells in response to extracellular nucleotides. Studying NaCl secretion in the colon, Jens Leipziger and colleagues focused on the P2Y6 receptor, which is expressed basolaterally in colonic enterocytes. As they report (pages 371-379), activation of the receptor by UDP leads to sustained NaCl secretion. Comparison with the P2Y1 receptor, which is expressed in a similar pattern, revealed that while ATP-induced activation of P2Y1 stimulates Ca2+-mediated secretion, UDP-mediated activation of P2Y6 elevates both Ca2+ and cytosolic cAMP levels. High cAMP levels in turn activate cAMP-regulated ion channels in the apical colonic mucosa, thus ensuring a sustained secretory response.
CONTACT:
Jens Leipziger
Institute of Physiology
Ole Worms Allé 160
Aarhus, NULL 8000
DENMARK
Phone 1: 45-89-422-826
Fax 1: 45-86-129-065
E-mail: leip@fi.au.dk
View the PDF of this article at: https://www.the-jci.org/press/16711.pdf
Mechanisms of diabetes suppression
The CD3 complex, a part of the T cell receptor, plays a central part in the antigen-specific activation of T cells. OKT3, a murine anti-CD3 antibody, has been shown to induce lasting remission of diabetes in mice when administered shortly after disease onset, and initial results with a modified version of the antibody in human patients were encouraging. Interested in the mechanism by which the antibody acts in humans, Kevan Herold and colleagues have examined the response of T cells to the modified antibody hOKT3gamma1(Ala-Ala). As they report, beginning on page 409, the structural alterations that lead to the humanized antibody that no longer binds Fc receptors seem to have changed the activation properties of hOKT3gamma1(Ala-Ala) compared with other anti-CD3 antibodies. hOKT3gamma1(Ala-Ala) treatment promotes the generation of IL-10 secreting T cells that might inhibit the autoimmune response and thus elicit beneficial effects in diabetes patients.
CONTACT:
Kevan Herold
Columbia University
1150 St Nicholas Ave
2nd floor
New York, NY 10032
USA
Phone 1: 212-305-5025
Fax 1: 212-304-5493
E-mail: kh318@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/16090.pdf
Complex channel genetics
Mutations in the SCN5A gene, which encodes a cardiac sodium channel, can cause multiple cardiac diseases including long QT and Brugada syndrome, depending on the resulting specific amino acid change. On pages 341-346, Jeffrey Balser and colleagues report on a boy with congenital heart disease. The patient is homozygous for a novel T512I mutation in SCN5A but also carries a common polymorphism (H558R, present in one out of five individuals) on one allele. In vitro comparison of channels encoded by either the allele containing the T512I alteration alone or the H558R/T512I allele revealed a direct functional interaction between the two alterations such that the effects of T512I alone are more severe than when they are present in the context of H558R. Additional examples will be necessary to test whether the common H558R alteration can modulate other SCN5A mutations that by themselves cause severe phenotypes.
CONTACT:
Jeffrey Balser
Vanderbilt University
560 Preston Research Building
2220 Pierce Avenue
Nashville, TN 37232-6602
USA
Phone 1: 615-936-0277
Fax 1: 615-936-2980
E-mail: jeff.balser@vanderbilt.edu
View the PDF of this article at: https://www.the-jci.org/press/16879.pdf
Endothelial lipase is a major determinant of HDL level
CONTACT:
Thomas Quertermous
Stanford University School of Medicine
Cardiovascular Medicine, Falk CVRC
300 Pasteur Drive
Stanford, CA 94305-5406
USA
Phone 1: 650-723-5013
Fax 1: 650-725-2178
E-mail: tomq1@stanford.edu
View the PDF of this article at: https://www.the-jci.org/press/16306.pdf
RELATED MANUSCRIPT
Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo
CONTACT:
Daniel J. Radar
University of Pennsylvania Medical Center
654 BRBII/III Labs
421 Curie Boulevard
Philadelphia, PA 19104-6160
USA
Phone 1: 215-573-4176
Fax 1: 215-573-8606
E-mail: rader@mail.med.upenn.edu
View the PDF of this article at: https://www.the-jci.org/press/16146.pdf
ACCOMPANYING COMMENTARY ON BOTH ARTICLES:
Endothelial Lipase: Direct Evidence For A Role in HDL Metabolism
CONTACT:
Jonathan C. Cohen
UT Southwestern Medical Center
Center For Human Nutrition
5323 Harry Hines Blvd.
Dallas, TX
USA
Phone 1: 214-648-4774
Fax 1: 214-648-4837
E-mail: Jonathan.Cohen@UTSouthwestern.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17744.pdf
Osteopetrosis and Thalamic Hypomyelinosis with Synaptic Degeneration in DAP12-Deficient Mice
CONTACT:
Toshiyuki Takai
Institute of Development, Aging and Cancer, Tohoku University
Seiryo 4-1
Sendai, NULL 980-8575
JAPAN
Phone 1: 81-22-717-8501
Fax 1: 81-22-717-8505
E-mail: tostakai@idac.tohoku.ac.jp
View the PDF of this article at: https://www.the-jci.org/press/16923.pdf
ACCOMPANYING COMMENTARY:
Dap 12 Signaling: From Immune Cells To Bone Modeling and Brain Myelinization
CONTACT:
Marco Colonna
Washington University, School of Medicine
Department of Pathology and Immunology
West Building, Room 1738
Box 8118, 660 South Euclid Ave
St. Louis, MO 63110
USA
Phone 1: 314-362-0367
Fax 1: 314-362-4096
E-mail: mcolonna@pathology.wustl.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17745.pdf
Costimulating Aberrant T Cell Responses by B7-H1 Autoantibodies in Rheumatoid Arthritis
CONTACT:
Lieping Chen
Mayo Clinic
Department of Immunology
200 First Street, SW
Rochester, MN 55905
USA
Phone 1: 507-538-0013
Fax 1: 507-284-1637
E-mail: chen.lieping@mayo.edu
View the PDF of this article at: https://www.the-jci.org/press/16015.pdf
**Please mention the Journal of Clinical Investigation as the source of these articles**
Journal
Journal of Clinical Investigation