[ Back to EurekAlert! ] Public release date: 15-May-2008
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Contact: Karen Honey
Journal of Clinical Investigation

JCI online early table of contents: May 15, 2008

EDITOR'S PICK: Look to the future: new drug reduces one cause of vision loss

In the industrialized world, most diseases that cause vision loss do so by altering the permeability of the blood vessels in the retina of the eye such that fluid accumulates in the retina impairing eyesight. For many of these diseases, the molecule VEGF is the initiator of increased blood vessel permeability and recent clinical data have indicated that VEGF antagonists can stabilize, or even improve, the eyesight of some patients. However, such treatment requires repeated injection of the VEGF antagonist into the eye. A potentially more painless and simple approach to reducing VEGF-induced blood vessel permeability in the eye has now been suggested by the work of Martin Friedlander and colleagues, at The Scripps Institute, La Jolla, in mouse and rabbit models of increased VEGF-mediated blood vessel permeability.

In the study, a small molecule inhibitor of the signaling molecules that associate with the receptors of VEGF (which are known as Src kinases) was found to eliminate VEGF-induced accumulation of fluid in the retina of mice and rabbits. This effect was observed both when the inhibitor was injected intravenously and when the inhibitor was administered in an eye drop. The specificity of the approach was confirmed by showing that the inhibitor did not prevent VEGF-induced accumulation of fluid in the retina of mice lacking the Src kinases that associate with the receptor of VEGF. The authors therefore suggest that future studies should investigate whether this approach would be of benefit to individuals with the many diseases that cause vision loss through VEGF-induced increased blood vessel permeability.

TITLE: Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits

Martin Friedlander
The Scripps Research Institute, La Jolla, California, USA.
Phone: (858) 784-9138; Fax: (858) 783-9135; E-mail: friedlan@scripps.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33361

CARDIOLOGY: Genetic mutation causes seizures and an irregular heartbeat

Exercise or becoming highly emotional can cause the heartbeat to become irregular, often causing sudden death, in individuals with an inherited heart disorder known as catecholaminergic polymorphic ventricular tachycardia (CPVT). The gene that is mutated in many individuals with CPVT carries the information for making a protein known as RyR2, which forms a channel through which Ca2+ passes. The genetic mutations in individuals with CPVT make the RyR2 channel leaky and this is thought to cause the potentially fatal irregular heartbeats. A large proportion of individuals with CPVT also suffer from seizures and these were thought to be caused by changes in the heartbeat. However, Andrew Marks and colleagues, at Columbia University College of Physicians and Surgeons, New York, have now generated data in mice indicating that the seizures are directly caused by leaky RyR2 channels.

In the study, mice engineered to express the leaky RyR2 channel found in some individuals with CPVT were observed to suffer exercise-induced changes in their heartbeat, sudden death due to such changes, and spontaneous seizures. Importantly, the seizures occurred in the absence of changes in the heartbeat and Ca2+ leak was detected in cells in the brain. Additional evidence that leaky RyR2 channels in the brain and heart cause seizures and irregular heartbeats, respectively, was provided by the demonstration that a molecule that prevents the mutant RyR2 channels from leaking but does not inhibit their normal function reduced the frequency and severity of the seizures as well as eliminated the exercise-induced changes in heartbeat.

TITLE: Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice

Andrew R. Marks
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 305-0270; Fax: (212) 305-3690; E-mail: arm42@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35346

CARDIOVASCULAR DISEASE: The protein NPC1 polices macrophage cholesterol traffic

Atherosclerosis is a disease of the arterial blood vessels that is often known as hardening of the arteries. It is caused in part by the accumulation in the artery wall of cells (mostly cells known as macrophages) that contain fats (mostly cholesterol). Understanding how macrophages regulate the amount and type of cholesterol they contain is therefore of importance for understanding the mechanisms underlying atherosclerosis. Daniel Ory and colleagues, at the University of Washington School of Medicine, St. Louis, have now provided new insight into this, showing that the protein NPC1 is a factor protecting mice from atherosclerosis through its function as a regulator of macrophage cholesterol trafficking.

Mice lacking LDLR develop atherosclerosis when fed a high-fat diet, but when the authors manipulated these mice such that their macrophages lacked both LDLR and NPC1 they developed atherosclerosis more rapidly. The accelerated atherosclerosis in the absence of NPC1 was associated with impaired cholesterol efflux from macrophages. Further analysis revealed that NPC1 was required for the generation of 27-hydroxycholsterol, which binds proteins known as LXRs, and for the LXR-dependent upregulation of proteins involved in cholesterol efflux. These data suggest that variation in NPC1 gene expression might affect how susceptible an individual is to developing atherosclerosis.

TITLE: Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking

Daniel S. Ory
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-8737; Fax: (314) 362-0186; E-mail: dory@wustl.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32561

VASCULAR BIOLOGY: Be selective when picking the form of the protein VEGF you use to grow new blood vessels

After an individual has been born, the development of new blood vessels, a process known as angiogenesis, is known to involve cells from the bone marrow. However, it is not known how these cells are recruited to the site of angiogenesis and what exactly they do when the get there. Mauro Giacca and colleagues, at the International Centre for Genetic Engineering and Biotechnology, Italy, have now provided insight into both these issues by engineering the skeletal muscle of mice to express proteins important in the process.

Adeno-associated virus vectors were used to express one form of the proangiogenic factor VEGF (VEGF165) in the skeletal muscle of mice. This induced substantial angiogenesis and the recruitment of cells originating from the bone marrow. The cells from the bone marrow expressed a protein known as NP-1, which interacts with VEGF165. Further analysis revealed that the bone marrow cells were not incorporated into the new blood vessels but were required to induce the activation and proliferation of resident smooth muscle cells, which were then incorporated into the forming blood vessels. As another form of VEGF (VEGF121) was unable to recruit bone marrow–derived cells expressing NP-1 and did not induce angiogenesis, this study has provided important information for researchers deciding which form of VEGF to use in gene therapy trials to induce therapeutic angiogenesis.

TITLE: Bone marrow cells recruited through the neuropilin-1 receptor promote arterial formation at the sites of adult neoangiogenesis in mice

Mauro Giacca
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
Phone: 39-040-375-7324; Fax: 39-040-375-7380; E-mail: giacca@icgeb.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32832

GENETICS: Mouse model might help individuals with the genetic disorder Costello syndrome

A team of researchers at the CSIC/University of Salamanca and the Centro Nacional de Investigaciones Oncológicas, Spain, has developed a new mouse model of Costello syndrome (CS) — an inherited disorder that affects many parts of the body, causing multiple symptoms; for example, effects on the brain and heart result in mental retardation and structural heart defects, respectively. The authors believe this new mouse model of CS will be useful for evaluating potential therapeutic strategies for individuals with CS, as there is currently no treatment for the disease.

CS is caused by mutations in the H-RAS gene, and the mouse model of CS was generated by engineering mice such that their H-Ras gene contained one of the mutations found in individuals with CS. The mice were found to have many, but not all, of the symptoms of CS. For example, they had abnormally shaped faces and heart defects. The mice also developed high blood pressure as they aged, something that has been documented for few individuals with CS (however, the author speculate that this might have gone undetected because most patients with CS do not undergo regular medical checkups after reaching adulthood). The high blood pressure was caused by abnormal upregulation of a protein known as Ang II and was prevented by treatment with a drug used to treat individuals with high blood pressure that inhibits the generation of Ang II. As some of the heart defects were also less severe after treatment with the drug, the authors suggested that some of the heart defects might be secondary changes in Ang II expression rather than direct effects of mutation of the H-RAS gene.

TITLE: A mouse model for Costello syndrome reveals an Ang II–mediated hypertensive condition

Xosé R. Bustelo
CSIC/University of Salamanca, Salamanca, Spain.
Phone: 34-923294802; Fax: 34-923294743; E-mail: xbustelo@usal.es.

Mariano Barbacid
Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
Phone: 34-912246938; Fax: 34-917328010; E-mail: mbarbacid@cnio.es.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34385

DEVELOPMENTAL BIOLOGY: Turn off gene regulators to tune in to development

For a fertilized egg to develop into an embryo a mass of identical cells must be directed to become a large number of distinct cell types with different functions and then these cells must be organized into functional organs and tissues. The proteins that direct these crucial events control the expression of an enormous number of genes and are known as transcription factors. Expression of transcription factors is itself tightly controlled and usually only occurs while the developmental step they regulate is taking place. Although many studies have established the importance of turning on a transcription factor at the correct time, few studies have investigated whether it is important when the transcription factor is turned off. However, new data, generated by Jonathan Epstein and colleagues, at the University of Pennsylvania, Philadelphia, have now indicated that inactivation of transcription factors is important for normal mouse development.

In the study, mice were engineered to express the transcription factor Pax3, which controls the development of cells known as neural crest cells into many different cell types (including some bone cells, some muscle cells, and some nerves), beyond the time it is normally shut off. Defects in craniofacial bone structures derived from neural crest cells were observed in these mice and they died within two days of birth due to cleft or shortened palates. Detailed analysis revealed that Pax3 prevented neural crest cells from responding to a factor that induces bone development (BMP-2), because it directly upregulated expression of the gene containing the information for making the protein Sostdc1, a soluble inhibitor of BMP signaling. The authors therefore conclude one function of Pax3 is to maintain neural crest cells in an undifferentiated state by preventing them from responding to factors that induce bone development.

TITLE: Persistent expression of Pax3 in the neural crest causes cleft palate and defective osteogenesis in mice

Jonathan A. Epstein
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-8731; Fax: (215) 573-9306; E-mail: epsteinj@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33715

BACTERIOLOGY: Helicobacter pylori help their cause by inducing the expression of molecules to which they bind

The bacterium Helicobacter pylori infects various parts of the stomach and small intestine, and chronic infection with H. pylori can cause stomach cancer. New insight into the mechanisms by which H. pylori modulates human stomach cells to increase its chances of successfully infecting those cells has been provided by Celso Reis and colleagues, at the University of Porto, Portugal.

To successfully infect the stomach H. pylori must adhere to the cells lining the stomach. One way in which it does this is to induce the cells lining the stomach to express a molecule known as sialyl–Lewis x, which binds to the H. pylori protein SabA. In the study, H. pylori was found to modify the expression of many genes by a human stomach cell line. However, the extent of the modification depended on how good the strain of H. pylori was at causing disease, those good at causing disease modified gene expression to a greater extent. Further, only those good at causing disease modified the expression of the gene carrying the information needed to make the protein beta-3GnT5, which is required for making sialyl–Lewis x. As cells engineered to express beta-3GnT5 showed increased expression of sialyl–Lewis x and increased adhesion to H. pylori, the authors concluded that they had uncovered one mechanism by which H. pylori modulates human stomach cells to increase its chances of establishing an infection.

TITLE: Helicobacter pylori induces beta-3GnT5 in human gastric cell lines, modulating expression of the SabA ligand sialyl–Lewis x

Celso A. Reis
University of Porto, Porto, Portugal.
Phone: 351-2255-70700; Fax: 351-2255-70799; E-mail: celso.reis@ipatimup.pt.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34324


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