NADH:ubiquinone oxidoreductase (complex I) of the electron transport chain is a multimeric mitochondrial enzyme of approximately 1000 kDa consisting of 46 different proteins encoded by both the mitochondrial and nuclear genomes. Little is known about the cellular mechanisms and protein chaperones that guide its assembly. In this issue of the JCI, Ogilvie et al. use genomic sequence data to compare the proteins produced by yeasts with and without complex I in order to generate a list of proteins whose human orthologs might serve as complex I assembly proteins. The gene encoding one of these candidate proteins, B17.2L, was found to harbor a nonsense mutation in one of 28 patients with a deficiency of complex I. B17.2L associated with subcomplexes that are seen when complex I assembly is incomplete. The research described here combines clever model organism genomics and bioinformatics with sophisticated human molecular and biochemical genetics to identify the first mammalian protein required for the normal assembly of complex I.
Robert L. Nussbaum
The pathobiology of pulmonary arterial hypertension (PAH) includes endothelial cell dysfunction and proliferation and migration of VSMCs. As PDGF has been implicated in these processes, Schermuly et al. hypothesized that altered PDGF signaling may be involved in the vascular remodeling observed in PAH. To explore this notion further, the authors evaluated the effects of the PDGF receptor inhibitor STI571 in 2 different animal models of pulmonary hypertension. In both models, after development of pulmonary vascular disease, administration of STI571 reversed pulmonary vascular changes. These studies provide preclinical proof of concept for the clinical development of a PDGF inhibitor as a targeted therapy for PAH patients.
Robyn J. Barst
APOA5 is a newly identified apolipoprotein that plays a crucial role in the regulation of plasma triglyceride levels. In several human studies, common APOA5 single nucleotide polymorphisms have been strongly associated with elevated plasma triglyceride levels. In this issue of the JCI, Marçais et al. report that the rare Q139X mutation in APOA5 leads to severe hypertriglyceridemia by exerting a dominant-negative effect on the plasma lipolytic system for triglyceride-rich lipoproteins. The presented data support the idea that the molecular mechanism of APOA5 function may include the enhancement of binding between lipoproteins and proteoglycans at the vascular wall and activation of proteoglycan-bound lipoprotein lipase.
Martin Merkel, Joerg Heeren
The amygdala is believed to play a key role in assigning emotional significance to specific sensory input, and conditions such as anxiety, autism, stress, and phobias are thought to be linked to its abnormal function. Growing evidence has also implicated the amygdala in mediation of the stress-dampening properties of alcohol. In this issue of the JCI, Pandey and colleagues identify a central amygdaloid signaling pathway involved in anxiety-like and alcohol-drinking behaviors in rats. They report that decreased phosphorylation of cAMP responsive element–binding protein (CREB) resulted in decreased neuropeptide Y (NPY) expression in the central amygdala of alcohol-preferring rats, causing high anxiety-like behavior. Alcohol intake by these animals was shown to increase PKA-dependent CREB phosphorylation and thereby NPY expression, subsequently ameliorating anxiety-like behavior. These provocative data suggest that a CREB-dependent neuromechanism underlies high anxiety-like and excessive alcohol-drinking behavior.
Gary Wand
Cholesterol efflux from macrophages, the first step in reverse cholesterol transport (RCT), is assumed to play a critical role in the pathogenesis of atherosclerosis. However, in vivo proof supporting this hypothesis is lacking, due to difficulties in determining the activity of this first step in RCT. In this issue of the JCI, Zhang et al. apply their recently developed method for measuring RCT in vivo to estimate RCT in mouse models with varying levels of HDL turnover. A surprisingly efficient clearance of cholesterol to feces is observed in mice overexpressing hepatic scavenger receptor class B type I (SR-BI), whereas in SR-BI–knockout mice, cholesterol clearance is diminished. The study demonstrates that hepatic SR-BI is a positive regulator of macrophage RCT in vivo.
Astrid E. van der Velde, Albert K. Groen
Lymphangiogenesis is associated with pathological processes such as the metastatic spread of carcinoma cells and organization of immunologically active lymphocytic infiltrates following organ transplantation. It has not yet been established whether expansion of the lymphatic vascular meshwork is driven by incorporation of progenitor cells or by local endothelial cell division. In this issue of the JCI, Maruyama et al. provide evidence that after mouse corneal transplant, CD11b+ macrophages infiltrate the corneal stroma and transdifferentiate into lymphatic endothelial cell clusters that join existing lymphatic vessels. In complementary in vitro experiments, murine peritoneal macrophages expressed lymphatic endothelial markers and formed vessel-like protrusions. These findings add yet another facet to the plasticity of macrophages, which are already known to transform from naive monocytes into VEGF-C–producing cells. Thus, macrophages support lymphangiogenesis in 2 different ways, either by transdifferentiating and directly incorporating into the endothelial layer or by stimulating division of preexistent local lymphatic endothelial cells.
Dontscho Kerjaschki
Ang II plays a key role in cardiovascular regulation and participates in vascular pathobiology, including inflammation and remodeling. Whether these tissue effects are mediated by direct Ang II actions or indirectly as a result of its influence on hemodynamics is being debated. In vitro data have shown that Ang II induces vascular cellular transcriptional activation and gene expression, but the mechanisms explaining its long-term tissue effects in vivo are relatively unknown. Do the multiple in vivo vascular activities elicited by Ang II (such as inflammation, fibrosis, and vascular cell hypertrophy/proliferation) occur via independent pathways, or do common transcription mechanisms mediate these multiple effects? In this issue, Zhan et al. identify Ets-1 as a critical downstream transcriptional mediator of vascular inflammation and remodeling in vivo; their data suggest that Ets-1 may be a common denominator of a complex process that involves multiple pathways previously considered to be mechanistically independent. Characterization of the critical transcription programs activated by Ang II in vivo and determination of the hierarchy of responses are vital to the understanding of the mechanism of vascular disease and to the development of therapies targeted at inhibiting the common transcription effectors of vascular pathology.
Victor J. Dzau, Marco Lopez-Ilasaca
Parathyroid hormone–related protein (PTHrP) acts as a paracrine regulator in several tissues, and its physiological roles also extend to bone. In this issue of the JCI, Miao et al. demonstrate that osteoblast-specific ablation of Pthrp in mice results in osteoporosis and impaired bone formation both in vivo and ex vivo. These mice recapitulate the phenotype of mice with haploinsufficiency of Pthrp. The findings demonstrate that PTHrP plays a central role in the physiological regulation of bone formation, by promoting recruitment and survival of osteoblasts, and probably plays a role in the physiological regulation of bone resorption, by enhancing osteoclast formation. This has implications for both our understanding of the pathogenesis of osteoporosis and its treatment.
T. John Martin
Group B Streptococcus (GBS) is an important cause of infections, including meningitis. The molecular events underlying its pathogenesis are poorly understood. A study in this issue of the JCI reports that the GBS invasion-associated gene (iagA) contributes to meningeal infection and virulence by facilitating invasion of the cells that compose the blood-brain barrier and of other host cells. The mechanism involved most likely relates to the gene product’s role in synthesis of a glycolipid anchor for a bacterial cell-surface entity that interacts directly with host cells.
Miriam J. Baron, Dennis L. Kasper
Invariant natural killer T (iNKT) cells are T lymphocytes that behave similarly to cells of the innate immune system. The glycolipid α-galactosylceramide (α-GalCer) is a potent and specific activator of mouse and human iNKT cells and has been used in cancer clinical trials to drive NKT cell–mediated immune responses. However, little is known about the dynamics of the iNKT cell response to α-GalCer in vivo. In this issue of the JCI, Parekh and colleagues demonstrate that administration of α-GalCer causes iNKT cells to become unresponsive, for at least 1 month, in mice. This leads us to ask, should sequential administration of α-GalCer still be used to activate iNKT cells given the anergic state it has been shown here to induce? This intriguing article raises the issue of the avoidance of anergy induction in the design of treatment regimens that use α-GalCer as a specific activator of iNKT cells.
Barbara A. Sullivan, Mitchell Kronenberg
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