EDITOR'S PICK
Genetic mutation alters response to heart failure drugs
The group of drugs known as beta blockers help slow nerve impulses traveling through the heart in order to reduce the heart's workload. This effect is achieved via their action on beta-adrenergic receptors present in cardiac cells. As such, beta blockers have become a mainstay of the treatment regimen for chronic heart failure. However, doctors have remained puzzled by the variable responses to some beta blockers among heart failure patients. In a study appearing in the January issue of the Journal of Clinical Investigation, Stefan Engelhardt and colleagues from the University of Würzburg, Germany, explain why some heart failure patients may respond better than others to certain beta blockers. The secret lies in a single amino acid change in the beta1-adrenergic receptor, that may differ from person to person, which alters the receptor's conformation and in doing so may alter the receptor's response to a given beta blocker.
Engelhardt and colleagues examined variant beta1-adrenergic receptors in which the amino acid at position 389 had been replaced by either an arginine or a glycine residue. The authors were able to directly assess, in real time, the effects of 3 different beta1-adrenergic receptor antagonists – bisoprolol, metoprolol, and carvedilol – on the Arg389 and Gly389 variant beta1-adrenergic receptors in rat cardiac cells. They found that while each of these drugs caused a conformational change in the receptors, the effect of bisoprolol and metoprolol was minor and did not noticeably differ between the Arg389 and Gly389 receptor variants. In contrast, carvedilol treatment induced a response from the Arg389 variant that was 2.5-fold that of the Gly389 variant. This was attributed to carvedilol's ability to induce a more extreme conformational change in the Arg389 variant of the receptor, resulting in significantly dampened cAMP signaling in cardiac cells.
In an accompanying commentary, Brent DeGeorge and Walter Koch from Thomas Jefferson University comment that "the implications of these findings are of potentially profound clinical importance when considering the interindividual and ethnic variation that occurs in response to beta-adrenergic receptor therapy in the treatment of heart failure." Furthermore, "It has been reported.. [that].. the Arg389 variant is 20% less common in black patients compared with non-black patients, and this may partially explain the poorer response to beta1-adrenergic receptor antagonists seen in blacks compared with that of the rest of the population."
Future work to characterize the effect of genetic mutations in these receptors and the role such mutations play in the receptor's (and hence a patient's) response to these drugs, may eventually lead to a situation in which doctors could prescribe drug treatment that is adapted according to each patient's own genetic makeup, bringing new meaning to the idea of personalized medicine for the treatment of heart failure and other cardiac disorders.
TITLE: Real-time optical recording of beta1-adrenergic receptor activation reveals supersensitivity of the Arg389 variant to carvedilol
AUTHOR CONTACT:
Stefan Engelhardt
University of Würzburg, Würzburg, Germany.
Phone: +49-931-201-48710; Fax: +49-931-201-48539; E-mail: stefan.engelhardt@virchow.uni-wuerzburg.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30012
ACCOMPANYING COMMENTARY
TITLE: Beta blocker specificity: a building block toward personalized medicine
AUTHOR CONTACT:
Walter Koch
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Phone: (215) 955-9982; Fax: (215) 503-5731; E-mail: walter.koch@jefferson.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30476
EDITOR'S PICK
Glucose levels trigger compensation for type 2 diabetics
Many individuals with type 2 diabetes are diabetic because the cells of their body no longer respond to the hormone insulin, which is crucial for lowering blood sugar levels (blood glucose levels). However, before individuals become clinically diabetic their body tries to compensate for the increasing resistance to the effects of insulin by increasing both the amount of insulin secreted and the mass of insulin-secreting cells (beta cells) in the pancreas. Several factors have been shown to induce an increase in beta-cell mass, but exactly what triggers this in individuals consuming a high-fat diet has not been clearly established.
In a study appearing in the January issue of the Journal of Clinical Investigation, Takashi Kadowaki and colleagues from the University of Tokyo, Japan, show that in mice with high-fat diet–induced insulin resistance, changes in glucose concentration are likely to be the main trigger of increased beta-cell mass. The beta-cell mass of mice expressing only one copy of the gene encoding the sensor of blood glucose levels, GCK (Gck-/- mice), showed little increase compared with wild-type mice fed a high-fat diet, and the mice developed diabetes. One important mediator of the beta-cell mass increase downstream of GCK sensing increased blood glucose levels, and was shown to be IRS2, as expression of IRS2 in Gck-/- mice partially prevented diabetes by increasing beta-cell mass. The authors therefore suggest that novel strategies to increase beta-cell mass to treat type 2 diabetes and overcome high-fat diet–induced insulin resistance might be developed if the mechanism linking GCK and IRS2 can be determined. However, in an accompanying commentary, Gordon Weir and Susan Bonner-Weir from the Joslin Diabetes Center remind us that before we develop new therapeutics "it is essential that glucose signals involved in beta-cell replication in both health and disease be carefully defined."
TITLE: Glucokinase and IRS-2 are required for compensatory beta-cell hyperplasia in response to high-fat diet–induced insulin resistance
AUTHOR CONTACT:
Takashi Kadowaki
University of Tokyo, Tokyo, Japan.
Phone: +81-3-5800-8815; Fax: +81-3-5800-9797; E-mail: kadowaki-3im@h.u-tokyo.ac.jp.
View the PDF of this article at: https://www.the-jci.org/article.php?id=17645
ACCOMPANYING COMMENTARY
TITLE: A dominant role for glucose in beta-cell compensation of insulin resistance
AUTHOR CONTACT:
Gordon C. Weir
Joslin Diabetes Center, Boston, Massachusetts, USA.
Phone: (617) 732-2581; Fax: (617) 732-2650; E-mail: gordon.weir@joslin.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30862
GASTROENTEROLOGY
Cell relocation fixes damage to the gut lining
The cells lining the intestine (epithelial cells) function as a barrier that keeps the contents of our intestines separate from our body tissues. Damage to the epithelial cell layer allows the contents of our intestines, including our gut bacteria, access to our tissues and bloodstream; large numbers of bacteria in the bloodstream can result in the life-threatening condition septicemia. Therefore, rapid repair of the epithelial cell layer after damage is essential. In a study appearing in the January issue of the Journal of Clinical Investigation, researchers from Washington University School of Medicine, St. Louis, have identified what they believe is a new mechanism by which the epithelial cell layer of the mouse intestine is repaired after damage.
Thaddeus Stappenbeck and colleagues showed that repair of the epithelial cell layer of the mouse rectum by proliferation of colonic epithelial progenitors (ColEPs) required the presence of two proteins -- Myd88 and Ptgs2. Myd88 is a signaling protein that was shown to be upstream of the requirement for Ptgs2. Surprisingly, Myd88 signaling did not induce increased expression of Ptgs2 and instead caused the relocation of Ptgs2-expressing stromal cells in the intestinal tissues to sites in the epithelial cell layer rich in ColEPs. Further studies will be required to determine whether the Ptgs2-expressing stromal cells directly or indirectly induce ColEP proliferation and whether similar cellular relocation mechanisms control progenitor cell proliferation in other tissues.
In an accompanying commentary, Seth Rakoff-Nahoum and Ruslan Medzhitov from Yale University School of Medicine, propose a model whereby damage to the epithelial cell layer of the intestine allows immune cells in the intestinal tissues to sense gut bacteria and initiate Myd88 signaling, which results in them instructing nearby Ptgs2-expressing stromal cells to relocate to sites in the epithelial cell layer rich in ColEPs.
TITLE: Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury
AUTHOR CONTACT:
Thaddeus S. Stappenbeck
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314)-362-4214; Fax: (314)-362-7487; E-mail: stappenb@pathology.wustl.edu.
Jim Dryden
Associate Director, Broadcast Services
Medical Public Affairs, Washington University, St. Louis, Missouri, USA
Phone: (314)-286-0110; Fax: (314)-286-0199; e-mail jdryden@wustl.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29159
ACCOMPANYING COMMENTARY
TITLE: Prostaglandin-secreting cells: a portable first aid kit for tissue repair
AUTHOR CONTACT:
Ruslan Medzhitov
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-7541; Fax: (203) 785-4461; E-mail: ruslan.medzhitov@yale.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30865
METABOLIC DISEASE
How to trap heart attack–inducing lipoproteins in the blood
Atherosclerosis is a disease of the blood vessels that causes many problems, including heart attacks. It is caused by a buildup of fat (lipid)-containing macrophages (the rubbish-collecting cells of the immune system) in the arteries. The presence in the blood of high levels of remnant lipoproteins, cholesterol-rich particles that are produced as the large lipoprotein complexes that transport lipids around the body are degraded, potently promotes the development of atherosclerosis. Therefore, understanding the mechanisms by which lipoprotein remnants are removed from the circulation is an area of intensive research and two studies appearing in the January issue of the Journal of Clinical Investigation provide new insights into these mechanisms.
Jeffrey Esko and colleagues from the University of California in San Diego show that in mice, under normal physiological conditions, molecules known as heparan sulphate proteoglycans on the surface of cells in the liver have a crucial role in removing remnant lipoproteins generated in both the intestine and liver from the blood. However, Helen Hobbs and colleagues show that mice lacking an adaptor protein (ARH) that associates with the receptor for bad cholesterol (LDL) are better at clearing remnant lipoproteins than mice lacking the LDL receptor (LDLR) itself. This indicates that the LDLR is important for remnant lipoprotein clearance under certain circumstances, but whether clearance is mediated directly or indirectly was not determined. Similarly, humans with a mutation in the gene encoding ARH (who suffer from autosomal recessive hypercholesterolemia) are able to clear remnant lipoproteins from the blood, whereas individuals with mutations in their genes encoding the LDLR (who suffer from familial hypercholesterolemia) are not.
In an accompanying commentary, Robert Mahley and Yadong Huang from the Gladstone Institute of Cardiovascular Disease discuss how these complex studies enhance our understanding of lipid clearance from the body and suggest that heparan sulfate proteoglycans might be "responsible for remnant [lipoprotein] uptake by hepatocytes in the presence of defective LDLR internalization."
TITLE: Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members
AUTHOR CONTACT:
Jeffrey D. Esko
University of California, San Diego, La Jolla, California, USA.
Phone: (858) 822-1100; Fax: (858) 534-5611; E-mail: jesko@ucsd.edu.
Joseph R. Bishop
University of California, San Diego, La Jolla, California, USA.
Phone: (858) 822-1041; Fax: (858) 534-5611; E-mail: bishopr@ucsd.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29154
RELATED MANUSCRIPT
TITLE: Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia
AUTHOR CONTACT:
Helen H. Hobbs
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214)-648-6724; Fax: (214)-648-7539; E-mail: helen.hobbs@utsouthwestern.edu.
Jonathan Cohen
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-4774; Fax: (214) 648-7539; Email: jonathan.cohen@utsouthwestern.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29415
ACCOMPANYING COMMENTARY
TITLE: Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing
AUTHOR CONTACT:
Robert W. Mahley
Gladstone Institute of Neurological Disease, San Francisco, California, USA.
Phone: (415) 734-2000; Fax: (415) 355-0820; E-mail: rmahley@gladstone.ucsf.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30889
ONCOLOGY
BCL2 reins in BIM, preventing leukemic cell death
Cancer is caused when a population of cells starts to grow in an inappropriate and uncontrolled manner. In many cancers the tumor cells express increased levels of a family of proteins (that includes BCL2 and MCL1) that protect them from a form of cell death known as apoptosis. Exactly how these proteins are important for tumor cell survival, and thereby inappropriate and uncontrolled growth, has not been completely clear.
In a study appearing in the January issue of the Journal of Clinical Investigation, Anthony Letai and colleagues from the Dana-Farber Cancer Institute in Boston developed a new technique, which they called 'BH3-profiling', to show that human chronic lymphocytic leukemia (CLL) cells depend on BCL2 for survival. CLL cells treated with a compound that antagonizes BCL2 (ABT-737) were found to undergo apoptosis. This compound was shown to work by disrupting the interaction of BCL2 with BIM, a protein that initiates apoptosis. The authors therefore suggest that the level of expression of anti-apoptotic BCL2 in a cell might not reliably predict the sensitivity of that cell to apoptosis-inducing stimuli, rather that the amount of free BCL2 able to mop up initiators of apoptosis such as BIM predicts this. In terms of CLL, if most BCL2 is bound to BIM then compounds such as ABT-737 that directly release the anti-apoptotic brake provided by BCL2 sequestration of BIM might provide effective therapeutics for the treatment of this cancer.
TITLE: Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737
AUTHOR CONTACT:
Anthony Letai,
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Phone: (617)-632-2348; Fax: (617)-582-8160; E-mail: Anthony_Letai@dfci.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28281
CARDIOVASCULAR BIOLOGY
Complex macrophage and monocyte interactions at work in atherosclerosis
Monocytes and macrophages are prominent cell types involved in the body's response to the development of atherosclerotic plaques – a build-up of cholesterol and fatty material within arteries due to the effects of the inflammatory condition atherosclerosis. Three independent studies appearing in the January issue of the Journal of Clinical Investigation provide evidence in animal models of genetic- and high-fat diet–induced disease that: (i) distinct subsets of monocytes give rise to the macrophages present in atherosclerotic plaques; (ii) there is differential expression of chemokine receptors on the surface of these cell subsets; and (iii) consumption of a high-fat diet causes a subset of macrophages not normally present in fatty tissue under normal dietary conditions to travel there and to behave differently.
In the first study, Mikael Pittet and colleagues from Massachusetts General Hospital demonstrate that a subset of monocytes that express a high level of a marker antigen, Ly-6C, give rise to macrophages present in atherosclerotic plaques. In the second related study, Gwendalyn Randolph and colleagues from Mount Sinai School of Medicine in New York show that monocyte subsets differentially expresses the chemokine receptors CCR2, CCR5, and CX3CR1 in order to enter atherosclerotic plaques. In the third of this trio of articles, Alan Saltiel and colleagues from the University of Michigan document that macrophages from fatty tissue, which accumulate during obesity and are implicated in the development of insulin resistance and diabetes, undergo phenotypic changes to become proinflammatory.
In an accompanying commentary, Siamon Gordon from the University of Oxford discusses how these three studies yield further insights into the complexity of monocytes and tissue macrophages during genetic- and high-fat diet–induced disease. He concludes that further investigation is required before different subsets of cells can be selectively, efficiently, and safely targeted for potential therapies for conditions such as atherosclerosis or insulin resistance.
TITLE: Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata
AUTHOR CONTACT:
Mikael Pittet
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 726-5788; Fax: (617) 726-5708; E-mail: mpittet@hms.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29950
RELATED MANUSCRIPT
TITLE: Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques
AUTHOR CONTACT:
Gwendalyn Randolph
Mount Sinai School of Medicine, New York, New York, USA.
Phone: (212) 659-8262; Fax: (212) 803-6740; E-mail: Gwendalyn.Randolph@mssm.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28549
RELATED MANUSCRIPT
TITLE: Obesity induces a phenotypic switch in adipose tissue macrophage polarization
AUTHOR CONTACT:
Alan Saltiel
University of Michigan, Ann Arbor, Michigan, USA.
Phone: (734) 615-9787; Fax: (734) 763-6492; E-mail: saltiel@lsi.umich.edu.
View the PDF of this article at:https://www.the-jci.org/article.php?id=29881
ACCOMPANYING COMMENTARY
TITLE: Macrophage heterogeneity and tissue lipids
AUTHOR CONTACT:
Siamon Gordon
University of Oxford, Oxford, United Kingdom.
Phone: +44-1865-275534; Fax: +44-1865-275515; E-mail: siamon.gordon@path.ox.ac.uk or christine.holt@path.ox.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30992
Journal
Journal of Clinical Investigation