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Keeping blood pressure in check
Hypertension - the presence of persistently high blood pressure – is a leading mortality risk factor in Western populations. More than half of Americans over 50 years of age have hypertension and almost one quarter of the US population (about 50 million people) experience hypertension to some degree.
The constriction and dilation of blood vessels is partially controlled by G protein–coupled receptors (GPCRs), which are activated by many important cardiovascular hormones. RGS proteins, a family of more than 20 regulators of GPCR signaling, promote the deactivation of GPCRs and therefore may have a role in the regulation of blood pressure.
Kendall Blumer and colleagues at the Washington University School of Medicine in St. Louis, Missouri, analyzed mice deficient in a specific member of this regulatory family - RGS2 - and found that these mice were strongly hypertensive and exhibited persistent vessel constriction. Pharmacological studies revealed that the loss of RGS2 slowed the termination of signals that induce blood vessel constriction. This suggests that abnormally prolonged GPCR signaling can contribute to the onset of high blood pressure. Genetic defects in humans that affect RGS2 function may therefore be novel risk factors for the development of hypertension.
In the same issue, Dr. Thomas Coffman from Duke University and the Veterans Administration Medical Center in Durham, North Carolina, states in his accompanying commentary that "the level of blood pressure elevation in the RGS2-deficient animals is quite striking". The researchers also found that even mice that retained one copy of the rgs2 gene were still unable to compensate for the loss of the RG2 protein, and presented with hypertension. "The presence of hypertension in these animals suggests that naturally occurring mutations that only incrementally affect the level of RGS2 protein may have a significant impact on blood pressure regulation. The studies clearly show that RGS2 is an important regulatory element", indicated Dr. Coffman. Identification of abnormalities in GPCR signaling may lead to new means of diagnosing genetic causes of hypertension and the development of suitable therapies.
CONTACT:
Kendall J. Blumer
Department of Cell Biology and Physiology
Washington University School of Medicine
660 S. Euclid Avenue
St. Louis, Missouri 63110
USA
PHONE: 314-362-1668
FAX: 314-362-7463
E-mail: kblumer@cellbio.wustl.edu
View the PDF of this article at: https://www.the-jci.org/press/15598.pdf
ACCOMPANYING COMMENTARY: RGS2: a "turn off" in hypertension
CONTACT:
Thomas M. Coffman
Durham Veterans Administration Medical Center
Building 6/Nephrology, Room 1100
508 Fulton Street
Durham, North Carolina 27705
USA
PHONE: 919-286-6947
FAX: 919-286-6879
E-mail: tcoffman@duke.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17836.pdf
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TABLE OF CONTENTS
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STAT3: tight import-export regulations
STATs, upon phosphorylation by cytokine receptors, translocate to the nucleus where they function as transcriptional regulators. Subsequent nuclear export ensures that the signal is transient and renders the STATs available for further rounds of signaling. Christian Schindler and colleagues have focused on the cellular whereabouts of STAT3. Their study (pages 553-559) – together with similar findings for STAT1– supports a model in which two mechanisms exist to promote nuclear import of STATs: a rapid one in response to receptor activation, and a second, phosphorylation-independent one, which is active in unstimulated cells. The latter pathway leads to nuclear accumulation of low levels of STATs in resting cells. For STAT3, there appears to be an active export pathway in resting cells as well, which opposes nuclear accumulation. This tight control suggests that regulation in resting cells of STAT3 target genes – which remain to be identified – is important.
CONTACT:
Christian Schindler
Columbia University
Departments of Medicine and Microbiology
HHSC-1212
701 West 168th St.
New York, NY 10032
USA
Phone 1: 212-305-6407
Phone 2: 212-305-5380
Fax 1: 212-543-0063
E-mail: cws4@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/15372.pdf
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Expression profile of Hodgkin lymphoma cells
Hodgkin lymphoma is characterized by the presence of malignant Hodgkin and Reed-Sternberg cells in the affected lymph nodes. These cells, most frequently derived from germinal center B cells, but sometimes from T cells, have a heterogeneous and poorly characterized phenotype. Attempting a systematic large-scale characterization of the disease-specific cells, Ralf Küppers and colleagues have compared their expression profiles with those of normal and malignant B cells (pages 529-537). Cell lines derived from Hodgkin patients clustered as a distinct entity, irrespective of their B or T cell origin, and their expression profile was most similar to EBV-transformed B cells and cell lines derived from diffuse large B cell lymphomas. A number of genes expressed specifically in the Hodgkin-derived lines have potential as diagnostic markers. Future experiments are necessary to determine whether the Hodgkin-specific genes play a role in the pathogenesis of the disease and could be targets for therapeutic intervention.
CONTACT:
Ralf Küppers
University of Cologne
Department of Internal Medicine I
LFI E4 R706
Joseph-Stelzmannstr. 9
Cologne, UNK 50931
GERMANY
Phone 1: 49-221-478-4490
Fax 1: 49-221-478-6383
E-mail: ralf.kuppers@uni-koeln.de
View the PDF of this article at: https://www.the-jci.org/press/16624.pdf
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Pref-1 and adipogenesis
The balance of signals experienced by preadipocytes influences whether these cells undergo adipogenesis. In addition to deriving from the endocrine system, these signals originate from the preadipocytes themselves or operate as part of a feedback loop involving mature adipocytes. Having previously cloned Pref-1, a gene expressed in preadipocytes but not mature adipocytes, Hei Sook Sul and colleagues now report (pages 453-461) that transgenic mice expressing the Pref-1 extracellular domain in adipocytes exhibited a decrease in total fat pad weight and a reduction of adipocyte markers, as well as hypertriglyceridemia, impaired glucose tolerance, and decreased insulin resistance. The same was true for mice expressing the transgene exclusively in the liver, suggesting that Pref-1 can function in an endocrine manner, and that the resulting loss of adipocyte function triggers metabolic abnormalities.
CONTACT:
Hei-Sook Sul
University of California at Berkley
Dept. of Nutritional Sciences
Morgan Hall
Berkeley, CA 94720
USA
Fax 1: 510-642-0535
E-mail: hsul@nature.berkeley.edu
View the PDF of this article at: https://www.the-jci.org/press/15924.pdf
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Histone acetylation and autoimmune disease
Systemic lupus erythematosus (SLE) is associated with changes in cytokine patterns which are thought to contribute to the immunopathogenesis seen in patients and mouse models of the disease. In MRL-lpr/lpr mice, which mimic some aspects of the human disease, activated splenic T cells produce elevated levels of specific cytokines that drive the aberrant immune response. Having previously shown that histone deacetylase inhibitors (HDIs) can alter cytokine expression in human SLE T cells, Nilamadhab Mishra and colleagues report now (pages 539-552) that HDI treatment of splenocytes from MRL-lpr/lpr mice resulted in downregulation of Th1 and Th2 cytokines without apparent effects on general gene expression. Moreover, MRL-lpr/lpr mice treated with HDIs showed an amelioration of their autoimmune symptoms, especially of glomerulonephritis. These preliminary results are encouraging and warrant further exploration of the therapeutic potential of HDIs in lupus and other autoimmune diseases.
CONTACT:
Nilamadhab Mishra
Wake Forest University School of Medicine
Medical Center Blvd
Winston Salem, NC 27157
USA
Phone 1: 336-716-6573
Fax 1: 336-716-9821
E-mail: nmishra@wfubmc.edu
View the PDF of this article at: https://www.the-jci.org/press/16153.pdf
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ECM organization and resistance to tumor growth
SPARC is a matricellular protein that modulates cellular interaction with the ECM during development, remodeling, and tissue repair. Interested in the contribution of endogenous SPARC to tumor growth and progression, E. Helene Sage and colleagues implanted tumors in SPARC-null (SP-/-) mice and observed a substantial increase in tumor size compared to controls (pages 487-495). Given that tumor progression is dependent upon the growth of new bloods vessels, the authors were surprised to find no difference in tumor vessel density or cell cycling between SP-/- and SP+/+ mice. They did however observe faulty deposition of collagen - the major structural protein of the ECM - in SP-/-mice, which may lead to decreased mechanical resistance to tumor growth and transport. The data suggest the importance of SPARC in the development of the ECM and subsequent control of tumor growth.
CONTACT:
E. Helene Sage
The Hope Heart Institute
1124 Columbia Street, Suite 723
Department of Vascular Biology
Seattle, WA 98104
USA
Phone 1: 206-903-2026
Fax 1: 206-903-2044
E-mail: hsage@hopeheart.org
View the PDF of this article at: https://www.the-jci.org/press/16804.pdf
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Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy
CONTACT:
Nigel A. Calcutt
University of California San Diego
Department of Pathology
La Jolla, California 92093-0612
USA
PHONE: 858-534-3309
FAX: 858-534-1886
E-mail: ncalcutt@ucsd.edu
View the PDF of this article at: https://www.the-jci.org/press/15792.pdf
ACCOMPANYING COMMENTARY:
Oxidative stress and diabetic neuropathy: a new understanding of an old problem
CONTACT:
Eva. L. Feldman
University Of Michigan
Dept. Of Neurology
4414 Kresge III, Box 0588
200 Zina Pitcher Place
Ann Arbor, Michigan 48109
USA
PHONE: 734-763-7274
FAX: 734-763-7275
E-mail: efeldman@umich.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17863.pdf
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Insulin Signaling is Required for Insulin's Direct and Indirect Action on Hepatic Glucose Production
CONTACT:
Ronald C. Kahn
Joslin Diabetes Center
One Joslin Place
Boston, MA 02215
USA
Phone 1: 617-732-2635
Fax 1: 617-732-2593
E-mail: Ron.Kahn@joslin.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/16426.pdf
ACCOMPANYING COMMENTARY:
Insulin's effect on glucose production - direct or indirect?
CONTACT:
Eugene J. Barrett
University of Virginia Health Sciences Center
Department of Internal Medicine
MR-4 Box 5116
Charlottesville, VA 22908
USA
Phone 1: 804-924-1175
Fax 1: 804-924-1284
E-mail: ejb8x@virginia.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17881.pdf
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A diet-induced increase in uncoupling protein 3 content does not affect mitochondrial function in vivo in human skeletal muscle
CONTACT:
M.K.C. Hesselink
Maastricht University
Department of Movement Sciences
PO Box 616
6200 MD Maastricht,
THE NETHERLANDS
Phone 1: 31-43-3881317
Fax 1: 31-43-367-0972
E-mail: matthijs.hesselink@bw.unimaas.nl
View the PDF of this article at: https://www.the-jci.org/press/16653.pdf
ACCOMPANYING COMMENTARY: Role of uncoupling protein 3 in human physiology
CONTACT:
Timothy Garvey
Medical Univ. of South Carolina
Division of Endocrinology, Diabetes & Med. Genetic
171 Ashley Avenue
Charleston, SC 29425
USA
Phone 1: 803-792-2529
Fax 1: 803-792-4114
E-mail: garveywt@musc.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17835.pdf
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Mutation causing severe myasthenia reveals functional asymmetry of AChR signature Cys-loops in agonist binding and gating
CONTACT:
Andrew G. Engel
Mayo Clinic
Department of Neurology
Rochester, MN 55905
USA
Phone 1: 507-284-5102
Fax 1: 507-284-5831
E-mail: age@mayo.edu
View the PDF of this article at: https://www.the-jci.org/press/16997.pdf
ACCOMPANYING COMMENTARY:
Insights into channel function via channel dysfunction
CONTACT:
Henry Lester
California Institute of Technology
Division of Biology
Fax 1: 818-564-8709
E-mail: lester@caltech.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17882.pdf
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The suppressors of cytokine signaling-1 (SOCS1) as novel therapeutic targets for enterovirus-induced cardiac injury
CONTACT:
Kirk Knowlton
Kirk U.
University of California, San Diego
Department of Medicine
9500 Gilman Drive
San Diego, CA 92093, 0613k
USA
Phone 1: 858-822-1363
Fax 1: 858-822-3027
E-mail: kknowlton@ucsd.edu
View the PDF of this article at: https://www.the-jci.org/press/16491.pdf
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Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells: an in vitro and in vivo study
CONTACT:
Kar Neng Lai
University of Hong Kong
Department of Medicine
Rm.411 Professorial Block
Queen Mary Hospital, Pokfulam Road
HONG KONG
Phone 1: 852-28554251
Fax 1: 852-28162863
E-mail: knlai@hku.hk
View the PDF of this article at: https://www.the-jci.org/press/16079.pdf
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**Please mention the Journal of Clinical Investigation as the source of these articles**
Journal
Journal of Clinical Investigation