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1.  GINA: making it safe to know what’s in your genes 
doi:10.1172/JCI36366
PMCID: PMC2439487  PMID: 18596906
2.  Molecular pathogenesis of pulmonary arterial hypertension 
The Journal of Clinical Investigation  2008;118(7):2372-2379.
Recent investigations have suggested that it might be possible to reverse the pathology of pulmonary arterial hypertension (PAH), a disorder that can be rapidly progressive and fatal despite current treatments including i.v. prostacyclin. This review will address the cellular and molecular processes implicated in clinical, genetic, and experimental studies as underlying the pulmonary vascular abnormalities associated with PAH. Emerging treatments are aimed at inducing apoptosis of abnormal vascular cells that obstruct blood flow and at promoting regeneration of “lost” distal vasculature.
doi:10.1172/JCI33452
PMCID: PMC2439479  PMID: 18596905
3.  William and Lawrence Bragg, father and son 
doi:10.1172/JCI36305
PMCID: PMC2439477
4.  In This Issue 
doi:10.1172/JCI36354
PMCID: PMC2439475
5.  Your inner fish 
doi:10.1172/JCI36104
PMCID: PMC2439464
6.  Publish or perish, but at what cost? 
The academic scientific enterprise rewards those with the longest CVs and the most publications. Under pressure to generate voluminous output, scientists often fall prey to double publishing, self plagiarism, and submitting the “minimal publishable unit.” Are these ethical gray areas, or true transgressions?
doi:10.1172/JCI36371
PMCID: PMC2439458  PMID: 18596904
7.  Revisiting leptin’s role in obesity and weight loss 
The Journal of Clinical Investigation  2008;118(7):2380-2383.
Maintenance of weight loss is often unsuccessful because of metabolic adaptations that conserve energy. Studies in rodents suggest that a reduction in leptin level during weight loss signals to the brain to increase feeding and decrease energy expenditure. In this issue of the JCI, Rosenbaum et al. examined this concept in obese patients who lost weight and were maintained at 10% below their initial weight (see the related article beginning on page 2583). Brain activity responses to visual food stimuli were visualized using functional MRI. Leptin levels fell during weight loss and increased brain activity in areas involved in emotional, cognitive, and sensory control of food intake. Restoration of leptin levels maintained weight loss and reversed the changes in brain activity. Thus, leptin is a critical factor linking reduced energy stores to eating behavior. Potentially, leptin therapy could sustain weight loss by overriding the tendency toward energy conservation.
doi:10.1172/JCI36284
PMCID: PMC2430504  PMID: 18568083
8.  Mechanisms of resistance to ErbB-targeted cancer therapeutics 
The Journal of Clinical Investigation  2008;118(7):2389-2392.
The ErbB receptors, such as EGFR, have been intensely pursued as targets for cancer therapeutics. However, a large percentage of patients who are initially responsive to ErbB-targeted therapies experience tumor recurrence and become refractory to therapy. In this issue of the JCI, Guix et al. demonstrate that downregulation of IGF-binding protein 3 (IGFBP-3) and -4, the negative regulators of IGF-I receptor signaling, contributes to the resistance of human squamous cell carcinomas to the EGFR inhibitor gefitinib (see the related article beginning on page 2609). Understanding the mechanisms involved in the resistance of some tumors to ErbB-targeted molecules may provide guidelines for developing more efficient therapeutic approaches.
doi:10.1172/JCI36260
PMCID: PMC2430503  PMID: 18568082
9.  Measles virus breaks through epithelial cell barriers to achieve transmission 
The Journal of Clinical Investigation  2008;118(7):2386-2389.
Measles is a highly contagious disease that causes immunosuppression in patients. Measles virus infection has been thought to begin in the respiratory epithelium and then spread to lymphoid tissue. In this issue of the JCI, Leonard et al. provide data to suggest an alternative model of measles virus pathogenesis (see the related article beginning on page 2448). In human primary epithelial cells and rhesus monkeys in vivo, the authors show that initial infection of respiratory epithelium is not necessary for the virus to enter the host but that viral entry into epithelial cells via interaction of the virus with a receptor located on the basolateral side of the epithelium is required for viral shedding into the airway and subsequent transmission.
doi:10.1172/JCI36251
PMCID: PMC2430502  PMID: 18568081
10.  How irritating: the role of TRPA1 in sensing cigarette smoke and aerogenic oxidants in the airways 
The Journal of Clinical Investigation  2008;118(7):2383-2386.
Airway irritants cause a variety of lung pathologies. Two separate studies, the first recently reported in the JCI by Bessac et al. and the second reported by Andrè et al. in the current issue of the JCI (see the related article beginning on page 2574), have identified irritants that activate transient receptor potential cation channel, subfamily A, member 1 (TRPA1) receptors in airway sensory neurons, resulting in neurogenic inflammation and respiratory hypersensitivity. The identification of TRPA1 activation by toxicants from cigarette smoke and polluted air, such as crotonaldehyde, acrolein, and oxidizing agents such as hydrogen peroxide, is an important finding. These two studies enhance our understanding of how pollution and cigarette smoke can damage airway function and will hopefully pave the way for the development of rational alternative therapeutics for such airway injury.
doi:10.1172/JCI36111
PMCID: PMC2430501  PMID: 18568080
11.  Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin 
The Journal of Clinical Investigation  2008;118(7):2438-2447.
Neutrophil granulocytes form the body’s first line of antibacterial defense, but they also contribute to tissue injury and noninfectious, chronic inflammation. Proteinase 3 (PR3) and neutrophil elastase (NE) are 2 abundant neutrophil serine proteases implicated in antimicrobial defense with overlapping and potentially redundant substrate specificity. Here, we unraveled a cooperative role for PR3 and NE in neutrophil activation and noninfectious inflammation in vivo, which we believe to be novel. Mice lacking both PR3 and NE demonstrated strongly diminished immune complex–mediated (IC-mediated) neutrophil infiltration in vivo as well as reduced activation of isolated neutrophils by ICs in vitro. In contrast, in mice lacking just NE, neutrophil recruitment to ICs was only marginally impaired. The defects in mice lacking both PR3 and NE were directly linked to the accumulation of antiinflammatory progranulin (PGRN). Both PR3 and NE cleaved PGRN in vitro and during neutrophil activation and inflammation in vivo. Local administration of recombinant PGRN potently inhibited neutrophilic inflammation in vivo, demonstrating that PGRN represents a crucial inflammation-suppressing mediator. We conclude that PR3 and NE enhance neutrophil-dependent inflammation by eliminating the local antiinflammatory activity of PGRN. Our results support the use of serine protease inhibitors as antiinflammatory agents.
doi:10.1172/JCI34694
PMCID: PMC2430496  PMID: 18568075
12.  Phosphorylation of GSK-3β by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes 
The Journal of Clinical Investigation  2008;118(7):2506-2515.
cGMP-dependent protein kinase II (cGKII; encoded by PRKG2) is a serine/threonine kinase that is critical for skeletal growth in mammals; in mice, cGKII deficiency results in dwarfism. Using radiographic analysis, we determined that this growth defect was a consequence of an elongated growth plate and impaired chondrocyte hypertrophy. To investigate the mechanism of cGKII-mediated chondrocyte hypertrophy, we performed a kinase substrate array and identified glycogen synthase kinase–3β (GSK-3β; encoded by Gsk3b) as a principal phosphorylation target of cGKII. In cultured mouse chondrocytes, phosphorylation-mediated inhibition of GSK-3β was associated with enhanced hypertrophic differentiation. Furthermore, cGKII induction of chondrocyte hypertrophy was suppressed by cotransfection with a phosphorylation-deficient mutant of GSK-3β. Analyses of mice with compound deficiencies in both protein kinases (Prkg2–/–Gsk3b+/–) demonstrated that the growth retardation and elongated growth plate associated with cGKII deficiency were partially rescued by haploinsufficiency of Gsk3b. We found that β-catenin levels decreased in Prkg2–/– mice, while overexpression of cGKII increased the accumulation and transactivation function of β-catenin in mouse chondroprogenitor ATDC5 cells. This effect was blocked by coexpression of phosphorylation-deficient GSK-3β. These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3β by cGKII.
doi:10.1172/JCI35243
PMCID: PMC2423867  PMID: 18551195
13.  The transcription factor IFN regulatory factor–4 controls experimental colitis in mice via T cell–derived IL-6 
The Journal of Clinical Investigation  2008;118(7):2415-2426.
The proinflammatory cytokine IL-6 seems to have an important role in the intestinal inflammation that characterizes inflammatory bowel diseases (IBDs) such as Crohn disease and ulcerative colitis. However, little is known about the molecular mechanisms regulating IL-6 production in IBD. Here, we assessed the role of the transcriptional regulator IFN regulatory factor–4 (IRF4) in this process. Patients with either Crohn disease or ulcerative colitis exhibited increased IRF4 expression in lamina propria CD3+ T cells as compared with control patients. Consistent with IRF4 having a regulatory function in T cells, in a mouse model of IBD whereby colitis is induced in RAG-deficient mice by transplantation with CD4+CD45RBhi T cells, adoptive transfer of wild-type but not IRF4-deficient T cells resulted in severe colitis. Furthermore, IRF4-deficient mice were protected from T cell–dependent chronic intestinal inflammation in trinitrobenzene sulfonic acid– and oxazolone-induced colitis. In addition, IRF4-deficient mice with induced colitis had reduced mucosal IL-6 production, and IRF4 was required for IL-6 production by mucosal CD90+ T cells, which it protected from apoptosis. Finally, the protective effect of IRF4 deficiency could be abrogated by systemic administration of either recombinant IL-6 or a combination of soluble IL-6 receptor (sIL-6R) plus IL-6 (hyper–IL-6). Taken together, our data identify IRF4 as a key regulator of mucosal IL-6 production in T cell–dependent experimental colitis and suggest that IRF4 might provide a therapeutic target for IBDs.
doi:10.1172/JCI33227
PMCID: PMC2413182  PMID: 18535667
14.  Genetic variants of miRNA sequences and non–small cell lung cancer survival 
The Journal of Clinical Investigation  2008;118(7):2600-2608.
Recent evidence indicates that small noncoding RNA molecules known as microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Mutation, misexpression, and altered mature miRNA processing are implicated in carcinogenesis and tumor progression. Because SNPs in pre-miRNAs could alter miRNA processing, expression, and/or binding to target mRNA, we conducted a systematic survey of common pre-miRNA SNPs and their surrounding regions and evaluated in detail the association of 4 of these SNPs with the survival of individuals with non–small cell lung cancer (NSCLC). When we assumed that disease susceptibility was inherited as a recessive phenotype, we found that the rs11614913 SNP in hsa-mir-196a2 was associated with survival in individuals with NSCLC. Specifically, survival was significantly decreased in individuals who were homozygous CC at SNP rs11614913. In the genotype-phenotype correlation analysis of 23 human lung cancer tissue samples, rs11614913 CC was associated with a statistically significant increase in mature hsa-mir-196a expression but not with changes in levels of the precursor, suggesting enhanced processing of the pre-miRNA to its mature form. Furthermore, binding assays revealed that the rs11614913 SNP can affect binding of mature hsa-mir-196a2-3p to its target mRNA. Therefore, the rs11614913 SNP in hsa-mir-196a2 may be a prognostic biomarker for NSCLC. Further characterization of miRNA SNPs may open new avenues for the study of cancer and therapeutic interventions.
doi:10.1172/JCI34934
PMCID: PMC2402113  PMID: 18521189
15.  Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke 
The Journal of Clinical Investigation  2008;118(7):2482-2495.
Murine olfactory ensheathing cells (OECs) promote central nervous system axonal regeneration in models of spinal cord injury. We investigated whether OECs could induce a neuroplastic effect to improve the neurological dysfunction caused by hypoxic/ischemic stress. In this study, human OECs/olfactory nerve fibroblasts (hOECs/ONFs) specifically secreted trophic factors including stromal cell–derived factor–1α (SDF-1α). Rats with intracerebral hOEC/ONF implantation showed more improvement on behavioral measures of neurological deficit following stroke than control rats. [18F]fluoro-2-deoxyglucose PET (FDG-PET) showed increased glucose metabolic activity in the hOEC/ONF-treated group compared with controls. In mice, transplanted hOECs/ONFs and endogenous homing stem cells including intrinsic neural progenitor cells and bone marrow stem cells colocalized with specific neural and vascular markers, indicating stem cell fusion. Both hOECs/ONFs and endogenous homing stem cells enhanced neuroplasticity in the rat and mouse ischemic brain. Upregulation of SDF-1α and CXCR4 in hOECs/ONFs promoted neurite outgrowth of cocultured primary cortical neurons under oxygen glucose deprivation conditions and in stroke animals through upregulation of cellular prion protein (PrPC) expression. Therefore, the upregulation of SDF-1α and the enhancement of CXCR4 and PrPC interaction induced by hOEC/ONF implantation mediated neuroplastic signals in response to hypoxia and ischemia.
doi:10.1172/JCI34363
PMCID: PMC2398740  PMID: 18596986
16.  Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice 
The Journal of Clinical Investigation  2008;118(7):2393-2403.
To meet tissue requirements for oxygen, capillaries must be properly distributed without excess or shortage. In this process, tissue oxygen concentration is well known to determine capillary density via the hypoxia-induced cascade, in which HIFs and VEGF play key roles. However, some additional mechanisms modulating this cascade are suggested to be involved in precise capillary network formation. Here, we showed that leukemia inhibitory factor (LIF) was predominantly expressed in developing endothelium, while its receptor was expressed in surrounding cells such as retinal astrocytes. The retinas of Lif–/– mice displayed increased microvessel density accompanied by sustained tip cell activity, due to increased VEGF expression by astrocytes in the vascularized area. Lif–/– mice resisted hyperoxygen insult in the oxygen-induced retinopathy model, whereas they paradoxically had increased numbers of neovascular tufts. In an in vitro study, LIF inhibited hypoxia-induced VEGF expression and proliferation in cultured astrocytes. Lif–/– mice also exhibited similarly increased microvessel density and upregulated VEGF in various tissues outside the retina. Together, these findings suggest that tissues and advancing vasculature communicate to ensure adequate vascularization using LIF as well as oxygen, which suggests a new strategy for antiangiogenic therapy in human diseases such as diabetic retinopathy and cancer.
doi:10.1172/JCI34882
PMCID: PMC2398738  PMID: 18521186
17.  Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II  
The Journal of Clinical Investigation  2008;118(7):2496-2505.
Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system–specific exon of the with-no-lysine(K)–1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII.
doi:10.1172/JCI34088
PMCID: PMC2398735  PMID: 18521183
18.  Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed 
The Journal of Clinical Investigation  2008;118(7):2448-2458.
The current model of measles virus (MV) pathogenesis implies that apical infection of airway epithelial cells precedes systemic spread. An alternative model suggests that primarily infected lymphatic cells carry MV to the basolateral surface of epithelial cells, supporting MV shedding into the airway lumen and contagion. This model predicts that a mutant MV, unable to enter cells through the unidentified epithelial cell receptor (EpR), would remain virulent but not be shed. To test this model, we identified residues of the MV attachment protein sustaining EpR-mediated cell fusion. These nonpolar or uncharged polar residues defined an area located near the binding site of the signaling lymphocytic activation molecule (SLAM), the receptor for MV on lymphatic cells. We then generated an EpR-blind virus maintaining SLAM-dependent cell entry and inoculated rhesus monkeys intranasally. Hosts infected with the selectively EpR-blind MV developed rash and anorexia while averaging slightly lower viremia than hosts infected with wild-type MV but did not shed virus in the airways. The mechanism restricting shedding was characterized using primary well-differentiated human airway epithelial cells. Wild-type MV infected columnar epithelial cells bearing tight junctions only when applied basolaterally, while the EpR-blind virus did not infect these cells. Thus, EpR is probably a basolateral protein, and infection of the airway epithelium is not essential for systemic spread and virulence of MV.
doi:10.1172/JCI35454
PMCID: PMC2430500  PMID: 18568079
19.  Leptin reverses weight loss–induced changes in regional neural activity responses to visual food stimuli 
The Journal of Clinical Investigation  2008;118(7):2583-2591.
Increased hunger and food intake during attempts to maintain weight loss are a critical problem in clinical management of obesity. To determine whether reduced body weight maintenance is accompanied by leptin-sensitive changes in neural activity in brain regions affecting regulatory and hedonic aspects of energy homeostasis, we examined brain region–specific neural activity elicited by food-related visual cues using functional MRI in 6 inpatient obese subjects. Subjects were assessed at their usual weight and, following stabilization at a 10% reduced body weight, while receiving either twice daily subcutaneous injections of leptin or placebo. Following weight loss, there were predictable changes in neural activity, many of which were reversed by leptin, in brain areas known to be involved in the regulatory, emotional, and cognitive control of food intake. Specifically, following weight loss there were leptin-reversible increases in neural activity in response to visual food cues in the brainstem, culmen, parahippocampal gyrus, inferior and middle frontal gyri, middle temporal gyrus, and lingual gyrus. There were also leptin-reversible decreases in activity in response to food cues in the hypothalamus, cingulate gyrus, and middle frontal gyrus. These data are consistent with a model of the weight-reduced state as one of relative leptin deficiency.
doi:10.1172/JCI35055
PMCID: PMC2430499  PMID: 18568078
20.  Cigarette smoke–induced neurogenic inflammation is mediated by α,β-unsaturated aldehydes and the TRPA1 receptor in rodents 
The Journal of Clinical Investigation  2008;118(7):2574-2582.
Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 α,β-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify α,β-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway neurogenic inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.
doi:10.1172/JCI34886
PMCID: PMC2430498  PMID: 18568077
21.  Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase–dependent DC functions and regulates experimental graft-versus-host disease in mice 
The Journal of Clinical Investigation  2008;118(7):2562-2573.
Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allostimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors reduced experimental graft-versus-host disease (GVHD) in a murine allogeneic BM transplantation model. Exposure of DCs to HDAC inhibitors increased expression of indoleamine 2,3-dioxygenase (IDO), a suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with DCs from IDO-deficient animals caused substantial reversal of HDAC inhibition–induced in vitro suppression of DC-stimulated responses. Direct injection of HDAC inhibitors early after allogeneic BM transplantation to chimeric animals whose BM-derived cells lacked IDO failed to protect from GVHD, demonstrating an in vivo functional role for IDO. Together, these data show that HDAC inhibitors regulate multiple DC functions through the induction of IDO and suggest that they may represent a novel class of agents to treat immune-mediated diseases.
doi:10.1172/JCI34712
PMCID: PMC2430497  PMID: 18568076
22.  Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins 
The Journal of Clinical Investigation  2008;118(7):2609-2619.
Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFR TKI gefitinib by generating gefitinib-resistant (GR) A431 squamous cancer cells. In GR cells, gefitinib reduced phosphorylation of EGFR, ErbB-3, and Erk but not Akt. These cells also showed hyperphosphorylation of the IGFI receptor (IGFIR) and constitutive association of IRS-1 with PI3K. Inhibition of IGFIR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit GR cell growth. Gene expression analyses revealed that GR cells exhibited markedly reduced IGF-binding protein 3 (IGFBP-3) and IGFBP-4 RNA. Addition of recombinant IGFBP-3 restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit cell growth. Finally, gefitinib treatment of mice with A431 xenografts in combination with an IGFIR-specific monoclonal antibody prevented tumor recurrence, whereas each drug given alone was unable to do so. These data suggest that loss of expression of IGFBPs in tumor cells treated with EGFR TKIs derepresses IGFIR signaling, which in turn mediates resistance to EGFR antagonists. Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation.
doi:10.1172/JCI34588
PMCID: PMC2430495  PMID: 18568074
23.  Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice 
The Journal of Clinical Investigation  2008;118(7):2404-2414.
Hedgehog (HH) signaling has emerged as a critical pathway involved in the pathogenesis of a variety of tumors. As a result, HH antagonists are currently being evaluated as potential anticancer therapeutics. Conversely, activation of HH signaling in the adult heart may be beneficial, as HH agonists have been shown to increase coronary vessel density and improve coronary function after myocardial infarction. To investigate a potential homeostatic role for HH signaling in the adult heart, we ablated endogenous HH signaling in murine myocardial and perivascular smooth muscle cells. HH signaling was required for proangiogenic gene expression and maintenance of the adult coronary vasculature in mice. In the absence of HH signaling, loss of coronary blood vessels led to tissue hypoxia, cardiomyocyte cell death, heart failure, and subsequent lethality. We further showed that HH signaling specifically controlled the survival of small coronary arteries and capillaries. Together, these data demonstrate that HH signaling is essential for cardiac function at the level of the coronary vasculature and caution against the use of HH antagonists in patients with prior or ongoing heart disease.
doi:10.1172/JCI34561
PMCID: PMC2430494  PMID: 18568073
24.  Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome 
The Journal of Clinical Investigation  2008;118(7):2552-2561.
Type 2 congenital long QT syndrome (LQT-2) is linked to mutations in the human ether a-go-go–related gene (HERG) and is characterized by rate-corrected QT interval (QTc) prolongation, ventricular arrhythmias, syncope, and sudden death. Recognized triggers of these cardiac events include emotional and acoustic stimuli. Here we investigated the repeated occurrence of fever-induced polymorphic ventricular tachycardia and ventricular fibrillation in 2 LQT-2 patients with A558P missense mutation in HERG. ECG analysis showed increased QTc with fever in both patients. WT, A558P, and WT+A558P HERG were expressed heterologously in HEK293 cells and were studied using biochemical and electrophysiological techniques. A558P proteins showed a trafficking-deficient phenotype. WT+A558P coexpression caused a dominant-negative effect, selectively accelerated the rate of channel inactivation, and reduced the temperature-dependent increase in the WT current. Thus, the WT+A558P current did not increase to the same extent as the WT current, leading to larger current density differences at higher temperatures. A similar temperature-dependent phenotype was seen for coexpression of the trafficking-deficient LQT-2 F640V mutation. We postulate that the weak increase in the HERG current density in WT-mutant coassembled channels contributes to the development of QTc prolongation and arrhythmias at febrile temperatures and suggest that fever is a potential trigger of life-threatening arrhythmias in LQT-2 patients.
doi:10.1172/JCI35337
PMCID: PMC2423868  PMID: 18551196
25.  Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia 
The Journal of Clinical Investigation  2008;118(7):2471-2481.
Stress-induced analgesia (SIA) is a key component of the defensive behavioral “fight-or-flight” response. Although the neural substrates of SIA are incompletely understood, previous studies have implicated the hypocretin/orexin (Hcrt) and nociceptin/orphanin FQ (N/OFQ) peptidergic systems in the regulation of SIA. Using immunohistochemistry in brain tissue from wild-type mice, we identified N/OFQ-containing fibers forming synaptic contacts with Hcrt neurons at both the light and electron microscopic levels. Patch clamp recordings in GFP-tagged mouse Hcrt neurons revealed that N/OFQ hyperpolarized, decreased input resistance, and blocked the firing of action potentials in Hcrt neurons. N/OFQ postsynaptic effects were consistent with opening of a G protein–regulated inwardly rectifying K+ (GIRK) channel. N/OFQ also modulated presynaptic release of GABA and glutamate onto Hcrt neurons in mouse hypothalamic slices. Orexin/ataxin-3 mice, in which the Hcrt neurons degenerate, did not exhibit SIA, although analgesia was induced by i.c.v. administration of Hcrt-1. N/OFQ blocked SIA in wild-type mice, while coadministration of Hcrt-1 overcame N/OFQ inhibition of SIA. These results establish what is, to our knowledge, a novel interaction between the N/OFQ and Hcrt systems in which the corticotropin-releasing factor and N/OFQ systems coordinately modulate the Hcrt neurons to regulate SIA.
doi:10.1172/JCI35115
PMCID: PMC2423866  PMID: 18551194

Results 1-25 (24846)