[ Back to EurekAlert! ] Public release date: 16-Mar-2009
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Contact: Karen Honey
Journal of Clinical Investigation

JCI online early table of contents: March 16, 2009

EDITOR'S PICK: New human genetic link to high levels of "good" cholesterol

HDL cholesterol (HDL-C), or "good" cholesterol, carries excess cholesterol – that might otherwise block arteries – from blood vessels back to the liver for processing and elimination. As such, individuals with high plasma HDL-C levels have a decreased risk of developing coronary artery disease. Genetics contribute to determining a person's plasma HDL-C level, and in a new JCI study Daniel Rader and colleagues from the University of Pennsylvania show that mutations in the LIPG gene, which codes for an enzyme known as endothelial lipase, result in high plasma HDL-C levels.

The authors examined the LIPG gene in 585 subjects of European ancestry and identified 10 people with previously unreported rare mutated forms of this gene that were unique to subjects with very high HDL-C levels. Further studies revealed that mutations in the LIPG gene that cause loss of endothelial lipase activity were the cause of increased plasma HDL-C levels. These data provide important human genetic evidence that inhibition of endothelial lipase is likely to raise HDL-C levels in humans. Whether or not the resulting increase in HDL-C level due to this inhibition would impact cardiovascular health requires further study.

TITLE: Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans

Daniel J. Rader
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-4176; Fax: (215) 573-8606; E-mail: rader@mail.med.upenn.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=37176

EDITOR'S PICK: Combination therapy restores T cell numbers in HIV-infected individuals

White blood cells known as CD4+ T cells are the main target of HIV. The virus hijacks these cells and replicates within them, which ultimately destroys the cell. This depletion of the T cell population represents a major blow to the immune system and puts HIV-infected individuals at increased risk of opportunistic infections. Treatment of HIV-infected individuals with a cocktail of drugs called combination antiretroviral therapy (c-ART) is able to restore the T cell population and help fight HIV infection, however not all patients respond to this therapy. The growth factor interleukin-7 (IL-7) is known to stimulate T cell production and survival, suggesting that IL-7 may help restore the T cell population during HIV infection.

In a new study published in the JCI, Yves Levy and colleagues at the University of Paris undertook a clinical trial to evaluate the safety and efficacy of repeated IL-7 therapy over a 16-day period in 13 c-ART–treated, HIV-infected patients that possessed low T cell counts despite successful suppression of virus levels with c-ART. In these individuals, IL-7 was well tolerated and boosted the number of CD4+ and CD8+ T cells, which were able to mount an immune response against HIV. These effects were observed for 48 weeks. The data suggest that HIV-infected patients may benefit from intermittent therapy with IL-7 in combination with c-ART.

TITLE: Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment

Yves Levy
University of Paris, Creteil, France.
Phone: 33-149-81-24-55; Fax: 33-149-81-24-69; E-mail: yves.levy@hmn.aphp.fr

View the PDF of this article at: https://www.the-jci.org/article.php?id=38052

CARDIOVASCULAR DISEASE:Understanding what triggers plaque rupture in advanced coronary artery disease

Atherosclerosis is a common arterial disease in which deposits of cholesterol, fat, smooth muscle cells, and macrophages form a plaque on the inner surfaces of arteries. Over time, a plaque can significantly reduce blood flow, and sudden rupture of artery plaque can lead to complete artery blockage, causing a heart attack or stroke. In their new study in the JCI, Tracie Seimon and colleagues at New York's Columbia University report that macrophage deficiency of p38-alpha mitogen-activated protein kinase (p38alpha MAPK) – a protein that helps cells respond to various stresses – promotes apoptosis (a form of cell death) in macrophages, and results in plaque necrosis in mice with advanced atherosclerosis. The data demonstrate that p38alpha MAPK may play a critical role in protecting macrophages from apoptosis (and ultimate plaque rupture) in advanced atherosclerotic lesions. Inhibitors of p38 are currently being tested in clinical trials as anti-inflammatory drugs for the treatment of rheumatoid arthritis, atherosclerosis, and Crohn disease. The data presented here raise the possibility that such inhibitors may promote macrophage death, plaque necrosis, and plaque rupture. As such, further studies are needed to determine the net effect of p38 inhibitors on atherosclerotic plaques and subsequent acute coronary events.

TITLE: Macrophage deficiency of p38alpha MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice

Tracie Seimon
Columbia University, New York, New York, USA.
Phone: (212) 305-5669; Fax: (212) 305-5052; E-mail: tad2105@columbia.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=37262

PULMONARY BIOLOGY: WISP1 involved in lung scarring in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) involves replacement of the air sacs of the lung with scar tissue, which limits the ability of the lung to transfer oxygen into the bloodstream. The cause of IPF is not known and patients do not respond to currently available therapies. Air sac cells known as alveolar epithelial type II (ATII) cells are dysfunctional in IPF, however the link between ATII cell dysfunction and the development of lung fibrosis is poorly understood. In their new study in the JCI, Oliver Eickelberg and colleagues at Ludwig Maximilians University in Munich, Germany, examine a mouse model of pulmonary fibrosis and humans with IPF and report increased and altered expression of the protein WISP1 (WNT1-inducible signaling protein𔂿) in ATII cells. Administration of antibodies that neutralize WISP1 reduced lung fibrosis, improved lung function, and increased survival in these mice. The results of this study identify WISP1 as a key regulator of ATII cell function and may therefore be a potential therapeutic target for the treatment of IPF.

TITLE: WNT1-inducible signaling protein𔂿 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis

Oliver Eickelberg
Ludwig Maximilians University, Munich, Germany.
Phone: 49-89-3187-2319; Fax: 49-89-3187-2400; E-mail: oliver.eickelberg@helmholtz-muenchen.de

View the PDF of this article at: https://www.the-jci.org/article.php?id=33950

ONCOLOGY: Insight into how a fusion gene promotes childhood leukemia

Fusion of the genes TEL and AML1 to form the TEL-AML1 fusion gene is a frequent genetic abnormality in childhood acute lymphoblastic leukemia. This mutation usually occurs before birth but can remain clinically silent for up to 15 years. Development of clinical leukemia requires the acquisition of one or more additional genetic mutations after birth, and previous studies have suggested that these mutations are linked to abnormal immune responses to infection. Researchers have sought to determine why the TEL-AML1 fusion event shows no clinical effect for more than a decade, and what properties of the TEL-AML1 protein are involved in the acquisition of secondary genetic mutations and the development of clinical leukemia.

Mel Greaves and colleagues from the Institute of Cancer Research in the United Kingdom now report in the JCI that dysregulation of a signaling pathway involving the growth factor TGF-beta is a critical component of TEM-AML1 function. TGF-beta normally regulates cell differentiation and self-renewal as well as immune and inflammatory responses. These authors show that certain mouse cells expressing TEL-AML1 proliferate at a slower rate than their parent cells, but that these cells as well as human cord blood progenitor cells expressing TEL-AML1 have a marked growth advantage in the presence of TGF-beta, compared to normal cells. These data suggest that loss of sensitivity to TGF-beta could be an important component of the function of TEL-AML1. The precise mechanism by which TEL-AML1 inhibits TGF-beta signaling is not yet clear, but the results of this study indicate that it involves TEL-AML1 binding to the TGF-beta target molecule Smad3. Further studies will be required to determine how cells expressing TEL-AML1 may be further selected by immune or inflammatory reactions.

TITLE: The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells

Mel Greaves
The Institute of Cancer Research, Surrey, United Kingdom.
Phone: 44-20-8722-4073; Fax: 44-20-8722-4074; E-mail: mel.greaves@icr.ac.uk

View the PDF of this article at: https://www.the-jci.org/article.php?id=36428

ONCOLOGY: Mouse model of acute megakaryoblastic leukemia provides insight into human disease

Acute megakaryoblastic leukemia (AMKL) is a rare form of malignant cancer of the bone marrow in which immature precursors of blood cells, known as megakaryoblasts, rapidly proliferate. Fusion of the OTT and MAL genes to form the fusion gene OTT-MAL is a frequent genetic abnormality in pediatric AMKL. The cellular mechanisms driving this transformation are not well understood and the lack of an animal model of this disease has hindered progress. Resulting from a collaborative research effort led by D. Gary Gilliland at Harvard University Medical School, a new study in the JCI reports the complete phenotypic characterization of a knockin mouse model of OTT-MAL AMKL. The authors show that OTT-MAL expression disrupts the activity of a molecule known as RBPJ in the Notch signaling pathway, causing abnormal fetal development of blood platelet precursor cells. Further studies demonstrated that cooperation between OTT-MAL and a mutation in the MPL oncogene resulted in the animals displaying all the features of human AMKL. The data suggest that specific targeting of the RBPJ and MPL signaling pathways could be of therapeutic value for human AMKL.

TITLE: The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model

Olivier A. Bernard
Hopital Necker, Paris, France.
Phone: 33-1-44-49-58-63; Fax: 33-1-42-19-27-40; E-mail: olivier.bernard@inserm.fr

D. Gary Gilliland
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 355-9092; Fax: (617) 355-9093; E-mail: ggilliland@rics.bwh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=35901

CARDIOLOGY: Understanding calcium signaling in the enlarged heart

The contraction and relaxation of cardiac muscle cells (cardiomyocytes) over the course of each heartbeat requires extreme changes in the concentration of calcium within cells. In this context, it is difficult to understand how calcium-dependent signaling inside the cell, which also initiates adverse changes like enlargement of the heart (cardiac hypertrophy), is regulated.

Proteins known as PMCAs (plasma membrane calcium-ATPases) are implicated in controlling calcium-dependent signaling at locations in the cardiac muscle cell membrane. In a new JCI study, Jeffrey Molkentin and colleagues from the University of Cincinnati, Ohio, show that, in mice, PMCA4b reduces local calcium levels such that signals involved in initiating cardiac hypertrophy are reduced. Analysis of mice engineered such that PMCA4b was expressed specifically in cardiomyocytes, demonstrated that the global calcium cycling that controls cardiomyocyte contraction occurred normally, as did exercise-induced hypertrophy (a reversible and not abnormal type of enlargement of the heart). By contrast, the mice showed reduced pathologic cardiac hypertrophy (an abnormal enlargement of the heart) in two models of the disease. After further studies, the authors suggest that PMCA4b functions in cardiomyocytes at the level of calcium signaling to regulate pathologic hypertrophy, possibly through signaling pathways involving the proteins calcineurin and NFAT.

TITLE: Plasma membrane Ca2+-ATPase isoform 4 antagonizes cardiac hypertrophy in association with calcineurin inhibition in rodents

Jeffrey Molkentin
University of Cincinnati, Cincinnati, Ohio, USA.
Phone: (513) 636-3557; Fax: (513) 636-5958; E-mail: jeff.molkentin@cchmc.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=36693

NEPHROLOGY: AT1 receptors inflame the kidney

The renin-angiotensin system (RAS) is a system that regulates blood pressure and fluid balance in the body. Renin, released by the kidneys when blood volume is low, stimulates the production of angiotensin, which causes blood vessels to constrict and blood pressure to rise. Recent studies have also suggested that RAS, acting primarily through type 1 angiotensin (AT1) receptors, may also modulate immune responses.

In their new JCI study, Thomas Coffman and colleagues from Duke University Medical Center, in Durham, North Carolina, investigated the role of AT1 receptors in kidney injury in mice with the inflammatory kidney disease autoimmune nephritis. The authors generated mice that inherently develop an autoimmune disease characterized by nephritis and that is similar to human lupus, and that also lacked the major mouse type 1 angiotensin receptor, AT1A. Surprisingly, AT1A deficiency did not protect against nephritis, but instead substantially accelerated kidney injury. Further studies revealed that disease acceleration was caused by activation of a residual AT1 isoform, AT1B, in the kidney. Interestingly, there was no observed increase in blood pressure in these animals. Blockade of these receptors in the glomerulus protected against kidney injury. Together, these studies suggest that activation of AT1 receptors in the kidney is sufficient to accelerate renal injury and inflammation in the absence of high blood pressure. As such, inhibition of RAS may help protect the kidney in patients with autoimmune disorders.

TITLE: Glomerular type 1 angiotensin receptors augment kidney injury and inflammatory in murine autoimmune nephritis

Thomas Coffman
Duke University Medical Center, Durham, North Carolina, USA.
Phone: (919) 286-6947; Fax: (919) 286-6879; E-mail: tcoffman@acpub.duke.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=34862


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