JCI table of contents: December 22, 2005

December 22, 2005


Enzyme triggers plaque rupture in hardened arteries, causing heart attack and stroke

University of Washington researchers have revealed that, in mice with atherosclerosis, it is the expression of an active form of the enzyme MMP-9, by macrophages located within plaque buildup in narrowed coronary arteries, that triggers plaque rupture. This rupture can cause blood clots and block blood flow to the heart and brain, causing a heart attack or stroke. The results appear online on December 22 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation.

Atherosclerosis involves the slow buildup of fatty substances, cholesterol, collagen and elastin fibers, macrophages, and other molecules in the arterial lining, which results in formation of a plaque that can partially or totally block the flow of blood. It has been previously suggested that macrophages play a key role in inducing plaque rupture as rupture-prone lesions have been shown to be macrophage-rich.

Elaine Raines and colleagues devised a strategy to overexpress matrix metalloproteinase-9 (MMP-9) in the macrophages of advanced atherosclerotic lesions in mice. The authors found that macrophages secreting an autoactivating form of MMP-9 enhanced elastin breakdown in the surrounding extracellular matrix that physically stabilizes the plaque, and consequently induced plaque rupture. MMP-9 and factors that regulate its activation may be potential therapeutic targets for stabilizing rupture-prone plaques.

TITLE: Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice

Elaine Raines
University of Washington, Seattle, Washington, USA
Phone: 206-341-5410; Fax: 206-341-5416; E-mail: ewraines@u.washington.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25074


Mice lacking FAK have a lot of heart, literally

Enlargement of the heart, also known as eccentric cardiac hypertrophy, is an adaptive response to a variety of stimuli, such as high blood pressure, that increase stress on the heart and can ultimately cause arrhythmia and heart failure. In a study appearing online on December 22 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, Jun-Lin Guan and colleagues from Cornell University created mice in which the enzyme focal adhesion kinase (FAK) was selectively inactivated in ventricular cardiac muscle cells. They found that, in reaction to stresses placed on the heart, these mice developed eccentric cardiac hypertrophy characterized by an increase in the volume of the left chamber of their hearts and fibrous tissue formation. At 9 months of age these animals spontaneously developed the same symptoms even in the absence of such cardiac stressors. The data suggest that FAK is an important regulator of heart enlargement in mice. The availability of these designer mice will also help researchers gain a better understanding of signaling pathways that regulate heart development and function.

TITLE: Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice

Jun-Lin Guan
Cornell University, Ithaca, New York, USA
Phone: 607-253-3586; Fax: 607-253-3708; E-mail: jg19@cornell.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24497


How ERK1/2 irks airways: implications for asthma

IL-13 plays an important role in chronic inflammatory diseases of the lungs such as asthma. It is widely believed that IL-13 mediates its proinflammatory effects via the STAT6 signaling pathway. However, in a study appearing online on December 22 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, Jack Elias and colleagues from Yale University examined mice genetically engineered to express IL-13 in their lungs and found that IL-13 triggered the activation of the protein kinase ERK1/2. Furthermore, activation of this important signaling pathway resulted in lung inflammation and occurred in a STAT6-independent manner. As exaggerated IL-13 production has been implicated in the pathogenesis of asthma, these studies suggest that interventions that control and/or prevent the ac

tivation of ERK1/2 may be beneficial. TITLE: ERK1/2 mitogen-activated protein kinase selectively mediates IL-13-induced lung inflammation and remodeling in vivo

Jack A. Elias
Yale University School of Medicine, New Haven, Connecticut, USA
Phone: 203-785-4163; Fax: 203-785-3826; E-mail: jack.elias@yale.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25711


Abnormal maturation of the perforin protein wreaks immune system havoc

Perforin, which is expressed by white blood cells, deals a fatal blow to foreign cells by inserting itself into the cell membrane to form a pore through which water enters and causes the cell to swell, burst, and die. In a study appearing online on December 22 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, Janos Sumegi and colleagues at Cincinnati Children's Hospital Medical Center expressed human perforin in rat cells and showed that different missense mutations in the human perforin gene underly differing degrees of maturation of the perforin protein, which results in immune dysregulation of varying degrees of severity.

In humans, missense mutations in perforin lead to a spectrum of disease including an increased risk for tumorigenesis as well as hemophagocytic lymphohistiocytosis, which is characterized by an excessive number of histiocytes and lymphocytes that can accumulate and damage healthy tissue. For what is believed to be the first time, Janos Sumegi and colleagues have been able to express human perforin in rat cells, in order to facilitate further study of this protein. Perforin is synthesized as an inactive precursor and must undergo proteolytic processing to achieve the active form. The authors analyzed 21 different missense mutations in human perforin and revealed that these mutations result in 3 different classes of perforin protein: (a) a protein with partial proteolytic maturation and variable cytotoxic function (Class 1); (b) a protein with no apparent proteolytic maturation (Class 2), and; (c) no recognizable forms of perforin and severely diminished cytotoxicity (Class 3). The authors conclude that different clinical manifestations of perforin missense mutations likely depend on the "dose" of mature perforin protein produced. These studies provide a basis for understanding the impact of missense mutations on the structure of the perforin protein and offer some insight into why individuals with perforins mutations may present with diverse clinical symptoms.

TITLE: Aberrant materation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis

Janos Sumegi
Cincinnati Children's Hospital Medial Center, Cincinnati, Ohio, USA
Phone: 513-636-5976; Fax: 513-636-3549; E-mail: Janos.Sumegi@cchmc.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=26217


RIP140 puts the brakes on fat cell metabolism in mice

Using a technique known as siRNA-mediated gene silencing, Michael Czech and colleagues from the University of Massachusetts examined genes that are highly expressed in mouse fat and muscle cells. The authors found that the protein RIP140 is an important negative regulator of insulin-stimulated glucose uptake and cellular respiration in fat cells, as well as whole-body glucose tolerance and energy expenditure in mice. Their study appears online on December 22 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation.

Many metabolic processes are controlled in part by nuclear receptors, however little is known about the role of nuclear receptor corepressors such as RIP140 in fat accumulation and energy dissipation. The absence of the RIP140 corepressor has been previously shown to result in increased expression of regulatory genes involved in energy metabolism. Mice lacking the protein RIP140 are unable to express key metabolic genes in fat tissue and as such they remain lean and resistant to high-fat diet-induced obesity. The broad negative regulation of multiple metabolic pathways in fat cells, as shown here by Czech et al., suggests that RIP140 may be a candidate therapeutic target for the syndromes of obesity and type 2 diabetes. TITLE: Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes

Michael P. Czech
University of Massachusetts Medical School, Worcester, Massachusetts, USA
Phone: 508-856-2254; Fax: 508-856-1617; E-mail: Michael.Czech@umassmed.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26040


Irs1 and Irs2 signaling proves essential for glucose metabolism and growth

In a study appearing online on December 22 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, Morris White and colleagues from Harvard Medical School delve further into how the proteins Irs1 and Irs2 regulate glucose metabolism in the liver as well as growth in mice.

Insulin receptor substrate (Irs) proteins are regarded as central mediators of insulin's metabolic actions however their functions are incompletely understood. To establish whether signals from Irs1 and 2 are involved in glucose metabolism in the liver the authors disrupted the Irs2 gene in the livers of healthy mice or in the livers of mice lacking the Irs1 gene in their whole body. The double knockout mice developed diabetes immediately after birth and had severely impaired growth. The authors also reported that the expression of hundreds of genes were altered in the double-knockout mice indicating that the signals delivered by Irs1 or Irs2 help regulate gene expression in the liver and coordinate growth and glucose metabolism. Delineating the balance between Irs1 and Irs2 signaling should allow researchers to better understand metabolic disease and its progression to diabetes.

TITLE: Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth

Morris F. White
Harvard Medical School, Boston, Massachusetts, USA
Phone: 617-919-2846; Fax: 617-730-0244; E-mail: morris.white@childrens.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25735

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