EDITOR'S PICK: How slow growth as a fetus can cause diabetes as an adult
Intrauterine growth retardation (IUGR), which results in a baby having a low weight at birth, has been linked to the development of type 2 diabetes in adulthood. It has been suggested that this is because the expression of key genes is altered during fetal development and that this affects disease susceptibility later in life. Evidence to support this hypothesis and indicating that the changes in gene expression might be permanent has now been provided by Rebecca Simmons and colleagues, at the University of Pennsylvania, Philadelphia, using a rat model of IUGR.
Pervious studies using the rat model of IUGR have shown decreased fetal expression of the gene Pdx1, which is critical for the development and function of the cells that become defective in type 2 diabetes (pancreatic beta-cells), and adult onset of diabetes. In this study, expression of Pdx1 was found to be reduced in pancreatic beta-cells throughout life following IUGR. The molecular mechanisms (known as epigenetic mechanisms because they affect gene expression without altering the information in the gene) that reduced Pdx1 expression in pancreatic beta-cells were found to change during development. One mechanism was observed in the fetus, one following birth, and one after the onset of diabetes in adulthood. Of interest, the mechanisms reducing Pdx1 gene expression in the fetus and following birth could be reversed, whereas those reducing Pdx1 gene expression in the adult were irreversible. These data provide new insight into the mechanisms by which diabetes develops in adulthood following IUGR.
TITLE: Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1
Rebecca A. Simmons
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 746-5139; Fax: (215) 573-7627; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33655
CARDIOLOGY: New gene linked to sudden irregular heartbeats
Individuals with Brugada syndrome and/or cardiac conduction disease are at increased risk of sudden death due to irregular heartbeats (also known as cardiac arrhythmias). Although mutations in the SCN5A gene (which carries the information required for a cell to make the protein Nav1.5, the alpha-subunit of the main sodium channel in the heart) can cause these syndromes, they are not detected in all patients. New data, generated by Connie Bezzina and colleagues, at the University of Amsterdam, The Netherlands, have now identified three mutations in another gene (SCN1B) as associated with Brugada syndrome and/or cardiac conduction disease in some individuals who lack SCN5A mutations.
The SCN1B gene carries the information required for making two related sodium channel beta-subunits known as beta-1 and beta-1B. In the study, expression of the intermediates that translate the genetic information into the beta-1 and beta-1B proteins was found to be high in normal human heart tissue, in particular in the cells that conduct the electrical impulses that coordinate the beating of the heart. This was consistent with the hypothesis that mutant forms of these proteins might cause cardiac arrhythmias and/or defective conduction of the electrical impulses that regulate the heartbeat (the defects that lead to Brugada syndrome and cardiac conductance disease). Functional evidence to support this hypothesis was provided by the observation that the mutant forms of beta-1 and beta-1B reduced Nav1.5 sodium currents in cell lines and led the authors to suggest that mutations in SCN1B can make individuals susceptible to Brugada syndrome and/or cardiac conductance disease.
TITLE: Sodium channel beta-1 subunit mutations associated with Brugada syndrome and cardiac conductance disease in humans
Connie R. Bezzina
University of Amsterdam, Amsterdam, The Netherlands.
Phone: 31-20-5665403; Fax: 31-20-6976177; E-mail: C.R.Bezzina@amc.uva.nl.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33891
CARDIOLOGY: Of mice, rabbits, and men: new rabbit model of sudden cardiac death provides insight into the human disease
Individuals with long QT syndrome (LQTS) are at increased risk of sudden death due to irregular heartbeats (also known as a cardiac arrhythmias). Although mutations in several genes have been shown to cause the disease, the most commonly affected genes are KCNQ1 and KCNH2. New insight into the mechanisms by which these mutations might produce an irregular heartbeat in humans has been provided by Gideon Koren and colleagues, at Brown University, Providence, who have generated two rabbit models of LQTS.
Although mouse models of LQTS have enhanced our understanding of many aspects of the disease, there are important differences between mice and humans that limit the applicability of some studies to individuals with LQTS. Many of these differences are not found in rabbits, the authors therefore generated rabbits expressing either KCNQ1 or KCNH2 mutants that generate proteins with the same functional defect as found in individuals with LQTS. The heart defects observed in the rabbits mirrored those observed in individuals with LQTS and more than 50% of the rabbits carrying the KCNH2 mutant died suddenly due to irregular heartbeats in their first year of life. The proteins generated by the KCNQ1 and KCNH2 mutants prevented proteins generated by the corresponding nonmutant form of the gene from working and, importantly, no compensation for the loss of function of either protein was observed. As compensation for the loss of function of the proteins generated by the KCNQ1 and KCNH2 mutants is observed in mouse models of LQTS these data provide important insight into the mechanisms underlying the disease.
TITLE: Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome
Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Phone: (401) 444-0392; Fax: (401) 444-4061; E-mail: Gideon_Koren@Brown.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33578
VASCULAR BIOLOGY: Itís a fix: the protein p21Cip1 helps repair damaged blood vessels
New insight into the molecular mechanisms controlling the repair of damaged blood vessels has been provided by studies in mice by Manfred Boehm and colleagues at the National Institutes of Health, Bethesda.
The repair of a damaged blood vessel involves both cells that reside in the blood vessel wall and inflammatory cells that infiltrate the blood vessel wall after it has been damaged. In this study, the repair of damaged arteries was found to be defective in mice lacking the protein p21Cip1. Specifically, smooth muscle cells residing in the wall of the artery were found to proliferate excessively and the number of inflammatory cells infiltrating the wall of the damaged artery was markedly greater than in normal mice. These effects were associated with increased production of the soluble factor SDF-1 by cells in the artery wall. Further analysis indicated that p21Cip1 inhibits a signaling molecule important for inducing SDF-1 production. These data indicate that p21Cip1 controls both the proliferation of cells in the wall of a damaged artery and their production of SDF-1, which attracts inflammatory cells because they express the molecule to which SDF-1 binds: CXCR4. Further, as the blood vessel repair seems to go awry in the disease of the arteries known as atherosclerosis (which causes narrowing of the arteries and heart attacks), the authors suggest that p21Cip1 and SDF-1 might have a pivotal role in the development of this disease.
TITLE: p21Cip1 modulates arterial wound repair through the stromal cellĖderived factor-1/CXCR4 axis in mice
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 435-7211; Fax: (301) 451-7090; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31244
PHYSIOLOGY: Two receptors affecting blood pressure are inextricably linked
Persistent high blood pressure (hypertension) puts an individual at increased risk of strokes, heart attacks, and heart failure. One cause of hypertension is decreased excretion of sodium in the urine, which increases the amount of sodium in the body fluids. This causes cells to release water, which increases blood pressure by accumulating in the blood and body fluids. The amount of sodium excreted in the urine is controlled by the response of the kidney to a number of hormones, some of which increase sodium excretion (e.g. dopamine) and some of which decrease it (e.g. Ang II). New data, generated in mice, by Pedro Jose and colleagues, at Georgetown University Medical Center, Washington, DC, have now shown that dopamine 5 receptor (D5R) negatively regulates expression of Ang II type 1 receptor (AT1R) such that the effects of changes in the expression and/or activity of D5R on blood pressure are compounded by changes in expression of AT1R. These data led the authors to suggest that targeting both or either of these receptors might be of benefit when designing approaches to optimize treatment for hypertension.
TITLE: Dopamine 5 receptor mediates Ang II type 1 receptor degradation via a ubiquitin-proteasome pathway in mice and human cells
Pedro A. Jose
Georgetown University Medical Center, Washington, DC, USA.
Phone: (202) 444-8675; Fax: (202) 444-7161; E-mail:email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33637
BONE BIOLOGY: Specific role for one member of the NF-kappa-B family of proteins in bone cell development
New data, generated in mice by Deborah Novack and colleagues, at Washington University School of Medicine, St. Louis, have provided insight into the molecular pathways that regulate the development of bone cells known as osteoclasts, which function to reduce bone mass and are responsible for the bone loss associated with diseases such as osteoporosis and rheumatoid arthritis.
In the study, precursors of osteoclasts that lacked one member of the NF-kappa-B family of proteins (RelA) were impaired in their ability to develop into osteoclasts when stimulated with RANKL, a factor that usually induces osteoclast development. This defect in osteoclast development was due to increased death of the osteoclast precursors, induced by a RANKL-activated JNK-Bid cell-death pathway. Only the RelA NF-kappa-B family member was able to block this pathway, indicating that other family members cannot perform this function. These data, defining a specific role for RelA in allowing efficient osteoclast development, have implications when considering whether targeting NF-kappa-B family members would be beneficial to individuals with inflammatory diseases such as rheumatoid arthritis.
TITLE: RelA/p65 promotes osteoclast differentiation by blocking a RANKL-induced apoptotic JNK pathway in mice
Deborah Veis Novack
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 454-8472; Fax: (314) 454-5047; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33392
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