Nitrite says NO to ischemia/reperfusion injury
Nitrite is a simple inorganic anion that is the end product of nitric oxide (NO) oxidation, and previously thought to have only limited biological activity. In a study appearing online on April 14 in advance of the print publication of the May issue of the Journal of Clinical Investigation, David Lefer and colleagues from Louisiana State University Health Sciences Center show that nitrite is a potent inhibitor of ischemia-reperfusion (I/R) injury in the liver and heart.
The researchers showed that nitrite therapy conferred a dose-dependent cell protective effect in mouse models of I/R injury, limiting cell death and preserving organ function. These effects are NO-dependent. The data demonstrate that nitrite could be used therapeutically for I/R disease, as it is already known that nitrite is safe, and it is an approved treatment for cyanide poisoning.
Nitrite therapy could potentially be used to prevent organ dysfunction following I/R injury to the heart or vasculature resulting from surgery or transplantation. Nitrite may also serve an endogenous protective mechanism that protects cells from severe stress.
TITLE: Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver
AUTHOR CONTACT:
David Lefer
LSU Health Sciences Center, Shreveport, LA USA
Phone: 318-675-6974; Fax: 318-675-4217; E-mail: dlefer@lsuhsc.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=22493
EDITORS' PICK
A big fat contribution to breast tumor growth
Increased adipose mass is associated with an elevated risk of breast cancer, but little was known about how fat cells actually contribute to carcinogenesis. In a study appearing online on April 14 in advance of the print publication of the May issue of the Journal of Clinical Investigation, Philipp Scherer and others aimed to identify factors that are secreted by adipocytes and which are present in breast cancer stromal tissue.
In particular, the researchers focus on the adipocyte-derived collagen VI and show that it is a critical factor that promotes early tumor growth within the mammary microenvironment in vivo. The authors show that collagen VI encourages proliferation and survival of malignant cells and mice that lack collagen VI have significantly reduced tumor growth. The authors show substantial enrichment of a fragment of collagen VI on the surface of human breast tumor cells. The same fragment had powerful growth-stimulatory effects on breast cancer cells in vitro.
This study provides the first evidence that the extracellular matrix protein collagen VI can modulate tumor behavior, and offers a potential link between the epidemiological association of increased adipocyte mass and breast cancer.
TITLE: Adipocyte-derived collagen VI affects early mammary tumor progression in vivo: Interaction in the tumor/stroma microenvironment
AUTHOR CONTACT:
Philipp E. Scherer
Albert Einstein College of Medicine, Bronx, NY USA
Phone: 718-430-2928; Fax: 718-430-8574; E-mail: scherer@aecom.yu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23424
NEUROLOGY
EBV inflames multiple sclerosis
Multiple sclerosis (MS) is an inflammatory disease of the brain and spinal cord, but its cause is still unknown. In a study appearing online on April 14 in advance of the print publication of the May issue of the Journal of Clinical Investigation, Bernhard Hemmer and colleagues examine immune responses in patients with MS. The researchers identify several antibodies in these patients and find that these antibodies specifically recognize two proteins of the Epstein Barr Virus (EBV). One of them is called EBNA-1 and the other is a novel, uncharacterized EBV protein called BRRF2. The number of immune cells that control EBV infection was also higher in MS patients, suggesting a profound difference in the response to EBV proteins between MS patients and healthy subjects. This data suggests that EBV is involved in the pathogenesis of MS by driving immune responses in the brain and spinal cord of MS patients. These findings may foster new therapeutic strategies in MS.
TITLE: Identification of latent Epstein-Barr virus proteins as putative targets of an immune response in multiple sclerosis
AUTHOR CONTACT:
Bernhard Hemmer
Heinrich Heine University, Duesseldorf, Germany
Phone: 49-2118119296; Fax: 49-2118118485; E-mail: bernhard.hemmer@uni-duesseldorf.de
View the PDF of this article at: https://www.the-jci.org/article.php?id=23661
PHYSIOLOGY
High-fat diets hard on (and harden) the vessels
Vascular calcification occurs in atherosclerosis and is commonly seen in aging, diabetes, kidney disease, and a host of other physiological abnormalities. It can lead to amputation and cardiovascular disease in patients with type 2 diabetes. In a study appearing online on April 14 in advance of the print publication of the May issue of the Journal of Clinical Investigation, Dwight Towler and colleagues from Washington University outline a novel feature in cardiovascular calcification. The researchers have previously shown that a high fat diet promotes cardiovascular calcification, with parallel increases in vascular proteins called BMP2 and Msx2. The authors now show that vascular cells expressing Msx2 upregulate another protein called Wnt. Using both in vitro and in vivo models, they show that Msx2-Wnt signaling contributes to calcification and vascular mineral deposition. This work provides a better understanding of how vascular calcification arises in response to diabetes and a high fat diet.
TITLE: Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals
AUTHOR CONTACT:
Dwight Towler
Washington University School of Medicine, St. Louis, MO USA
Phone: 314-454-7434; Fax: 314-454-8434; E-mail: dtowler@im.wustl.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24140
PHYSIOLOGY
BH4 rescues a bruised heart B4 breaking
Heart failure can result from chronic hypertension, pressure overload and consequent overgrowth of the organ. In a study appearing online on April 14 in advance of the print publication of the May issue of the Journal of Clinical Investigation, David Kass and colleagues from Johns Hopkins Medical Institutes show that pressure overload causes a protein in the heart, called NOS3, to become a major source of damaging reactive oxygen species. The authors showed that treatment with BH4 inhibited ROS generation and cardiac hypertrophy. These data suggest that BH4, which is already being tested for hypertension, may be useful for decreasing the damage of hypertrophy and preventing consequent heart failure.
TITLE: Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure-load
AUTHOR CONTACT:
David A. Kass
Johns Hopkins University, Baltimore, MD USA
Phone: 410-955-7153; Fax: 410-502-2558; E-mail: dkass@jhmi.edu OR dkass@bme.jhu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=21968
ALSO IN THIS ISSUE
Keeping inflammation at bay
Regulation of the inflammatory response is critical. In a study appearing online on April 14 in advance of the print publication of the May issue of the Journal of Clinical Investigation, researchers find that a protein called thrombomodulin has unique anti-inflammatory properties and may be used therapuetically.
TITLE: The N-terminal Domain of Thrombomodulin Sequesters HMGB1: A Novel Anti-inflammatory Mechanism.
AUTHOR CONTACT:
Kazuhiro Abeyama
Kagoshima University, Kagoshima, Japan
Phone: 81-99-275-5437; Fax: 81-99-275-2629; E-mail: k-abeyam@m3.kufm.kagoshima-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/article.php?id=22782
ALSO IN THIS ISSUE
Organ-specific iron transport
Slc11a2 imports iron into cells. In a study appearing online on April 14 in advance of the print publication of the May issue of the Journal of Clinical Investigation, researchers developed mice lacking Slc11a2 and confirmed that Slc11a2 is required for iron absorption and utilization in the intestine. But, it is not required for placental iron transfer or for iron uptake by liver cells. The existence of alternative iron uptake mechanisms in these tissues suggests that there is at least one major iron importer yet to be discovered. This data advances understanding of iron homeostasis.
TITLE: Slc11a2 is required for iron absorption and erythropoiesis but dispensable in placenta and liver
AUTHOR CONTACT:
Nancy Andrews
Harvard Medical School, Boston, MA USA
Phone: 617-919-2116; Fax: 617-432-3639; E-mail: nandrews@enders.tch.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24356
Journal
Journal of Clinical Investigation