HDL has a key role in reverse cholesterol transport, mobilizing cholesterol from the peripheral tissues to liver. In this process, the ABC transporter A1 (ABCA1) protein controls the efflux of intracellular cholesterol to apoAI, the major apolipoprotein of HDL. Since ABCA1 mutations were discovered to cause Tangier disease, a rare recessive HDL deficiency, it has been speculated that sequence variants in ABCA1 might also contribute to variations in plasma HDL cholesterol levels in the general population. A new study provides genetic evidence supporting this hypothesis.
Päivi Pajukanta
Angiogenesis is regulated in large part by the balance of various proangiogenic stimulators, such as VEGF, and a diverse group of endogenous inhibitors of angiogenesis, most of which are extrinsic to endothelial cells. With respect to the latter, until recently, none have appeared to be induced as a consequence of a specific, self-regulating, feedback inhibition response. A new inhibitor, called vasohibin, has been uncovered. Vasohibin is selectively induced in endothelial cells by proangiogenic stimulatory growth factors such as VEGF; it appears to operate as an intrinsic and highly specific feedback inhibitor of activated endothelial cells engaged in the process of angiogenesis.
Robert S. Kerbel
The etiology of type 2 diabetes is characterized by obesity, insulin and leptin resistance, and compensatory β cell hyperplasia followed by islet degeneration, resulting in the eventual dysregulation of glucose and lipid homeostasis. The recent identification of insulin receptor substrate 2 (IRS2) as a central player in the pathophysiology of many of these processes suggests a potentially unifying molecular link underlying the initiation and progression of type 2 diabetes.
Matthew J. Brady
Hemoglobinopathies are caused by abnormal structure or synthesis of hemoglobin chains and represent serious monogenic disorders. A new study demonstrates that lentiviral vectors can express clinically relevant levels of human transgenic β-globin in red cells of xenografted mice. While some safety concerns must be addressed, this study is an important step toward potential clinical trials of gene therapy for hemoglobinopathies.
Christof von Kalle, Christopher Baum, David A. Williams
It has been difficult to develop therapies that target those T cells initiating and mediating the pathogenesis of autoimmune disease. Indeed, most current treatments indiscriminately affect both the autoreactive T cells and the “good” T cells, putting the patient at risk of compromised immune function. A new approach raises the possibility of targeted therapy for autoimmunity. Transplantation of hematopoietic stem cells modified to express a protective form of MHC class II corrects a defect in central tolerance. This method contrasts with other targeted therapies that attempt to modify peripheral tolerance, which is also defective in type 1 diabetes mellitus.
Rémi J. Creusot, C. Garrison Fathman
The production of protective neutralizing antibodies occurs quickly in some viral infections but very slowly in others. In a new study, surface glycoproteins (the targets of neutralization) of 2 different viruses were genetically switched. Analysis of the neutralizing antibody response to each of the 2 parent and recombinant viruses in infected mice revealed that the speed of neutralizing antibody induction was intrinsically dependent on the surface glycoprotein and not the rest of the virus.
Eva Szomolanyi-Tsuda, Raymond M. Welsh
Retinitis pigmentosa is a heritable group of blinding diseases resulting from loss of photoreceptors, primarily rods and secondarily cones, that mediate central vision. Loss of retinal vasculature is a presumed metabolic consequence of photoreceptor degeneration. A new study shows that autologous bone marrow–derived lineage-negative hematopoietic stem cells, which incorporate into the degenerating blood vessels in two murine models of retinitis pigmentosa, rd1 and rd10, prevent cone loss. The use of autologous bone marrow might avoid problems with rejection while preserving central cone vision in a wide variety of genetically disparate retinal degenerative diseases.
Lois E.H. Smith
Members of the family of prostanoids, made up of prostaglandins and thromboxanes, are generated via COX-mediated metabolism of arachidonic acid. These lipid mediators exhibit wide-ranging biological actions that include regulating both vasomotor tone and renal sodium excretion. As COX inhibition is often associated with sodium retention leading to edema and hypertension, prostanoids appear to have a role in preventing the development of high blood pressure. On the other hand, prostaglandin E2 (PGE2) and PGI2 have also been implicated as determinants of renin secretion. A new study suggests that PGI2 plays a critical role in stimulating renin release and promoting hypertension following renal artery stenosis.
Helene Francois, Thomas M. Coffman
Finding mutations in nuclear genes responsible for disorders in the mitochondrial oxidative phosphorylation system has been a tedious matter. A “Venn diagram” approach — not unlike a classic complementation experiment — reported in this issue will now make the search easier.
Eric A. Schon
Vascularized organ transplants often fail because of smooth muscle cell migration and proliferation in the intima of graft arteries, leading to progressive lumenal narrowing and resultant ischemic damage. Graft arterial disease is caused by IFN-γ secreted by alloreactive T cells. New evidence indicates that IFN-γ dysregulates expression of the enzymes eNOS and iNOS in graft-infiltrating leukocytes. Dysregulated NO synthase expression occurs prior to and is causally linked to intimal smooth muscle cell accumulation.
Richard N. Mitchell, Andrew H. Lichtman
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