Arrhythmias: how the mitochondria can break the heart
In a paper appearing online on November 10 in advance of print publication of the December issue of the Journal of Clinical Investigation, Brian O'Rourke and colleagues from Johns Hopkins University describe how failure of the mitochondrial network at the muscle-cell level leads to differential electrical excitability in hearts subjected to ischemia and reperfusion.
This work introduces a new mechanism to explain post-ischemic arrhythmias, in which disturbed mitochondrial function in clusters of cells in the reperfused heart leads to regional current sinks that prevent propagation.
The authors show that stabilizing mitochondrial membrane potential stabilizes the cellular action potential (AP), blunts AP shortening during ischemia, and prevents ventricular arrhythmias during reperfusion. This work could explain ischemia-related arrhythmias and explores the therapeutic potential of a compound targeting the mitochondria.
TITLE: The mitochondrial origin of post-ischemic arrhythmias
Johns Hopkins University, Baltimore, MD USA
View the PDF of this article at: https://www.the-jci.org/article.php?id=25371
Reversing obesity and diabetes works when leptin signaling is on the brain
Leptin is a hormone derived from fat cells, and defects in leptin signaling leads to obesity, overeating, and decreased energy output. Leptin signals through the leptin receptor, LEPR.
In a paper appearing online on November 10 in advance of print publication of the December issue of the Journal of Clinical Investigation, Streamson Chua and colleagues use transgenic mice to show that only one isoform of leptin receptor, LEPR-B, expressed exclusively in neurons, is sufficient to produce normal body composition and normal body weight. Brain specific leptin signaling was sufficient to reverse the obesity, diabetes, and infertility seen in db/db mice, which carry a defective leptin receptor.
This data provides evidence that leptin's effects on body composition, insulin sensitivity, and fertility are mediated by the nervous system and that the extraneural effects of leptin, with regard to body composition and insulin sensitivity, may be limited.
TITLE: Complete rescue of obesity/diabetes and infertility in db/db mice with neuron-specific LEPR-B transgenes
Streamson C. Chua, Jr.
Albert Einstein College of Medicine, New York, NY USA
View the PDF of this article at: https://www.the-jci.org/article.php?id=24059
New target in autoimmune skin blistering disease pops up
For decades, intravenous Ig has been used to treat a variety of immune and inflammatory diseases and numerous mechanisms have been proposed to explain its mode of action. Studies using animal models of autoimmune skin blistering diseases suggested that intravenous Ig protects against these autoimmune diseases as well.
In a paper appearing online on November 10 in advance of print publication of the December issue of the Journal of Clinical Investigation, Zhi Liu and colleagues from the University of North Carolina demonstrate a common mechanism for intravenous Ig activity in three autoimmune blistering disease models, which have distinct disease pathology - bullous pemphigoid (BP), pemphigus foliaceus (PF), and pemphigus vulgaris (PV). The authors show that intravenous Ig accelerates the degradation of pathogenic autoantibodies and prevents blistering. It does this by saturating the Fc receptor, FcRn.
The results give new insights into the pathology of these types of diseases and suggest that FcRn is a promising therapeutic target for treating such IgG-mediated autoimmune diseases.
TITLE: Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases
University of North Carolina Chapel Hill, NC USA
View the PDF of this article at: https://www.the-jci.org/article.php?id=24394
Coughing up a new player in emphysema
The cytokine IFN-gamma helps regulate the immune response. Dysregulated IFN-gamma is associated with many diseases where inflammation and remodeling take place, including atherosclerosis, rheumatoid arthritis, and pulmonary emphysema. However, the mechanism whereby IFN-gamma mediates these tissue changes has not been clear.
In a paper appearing online on November 10 in advance of print publication of the December issue of the Journal of Clinical Investigation, Jack Elias and colleagues from Yale University show that that a receptor called CCR5 plays a key role in the pathogenesis of IFN-gamma-induced and cigarette smoke-induced inflammation, tissue remodeling and emphysema.
Using mouse models, the authors demonstrate that IFN-gamma is a potent stimulator of a variety of chemokines – chemical mediators produced in inflammation that mobilize and activate white blood cells. Inactivating CCR5 decreases IFN-gamma-induced inflammation.
Further, the authors show that emphysema due to cigarette smoke exposure occurs via IFN-gamma-dependent mechanisms and this response is decreased in mice lacking CCR5. These studies highlight the importance of CCR5 in the pathogenesis of IFN-gamma-induced and cigarette smoke-induced changes in lung tissue.
TITLE: Role of CCR5 in IFN-gamma-induced and cigarette smoke-induced emphysema
Jack A. Elias
Yale University School of Medicine, New Haven, CT USA
View the PDF of this article at: https://www.the-jci.org/article.php?id=24858
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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