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Issue published October 15, 2004 Previous issue | Next issue

  • Volume 114, Issue 8
Go to section:
  • In this issue
  • Editorial
  • Historical Highlights
  • Retrospectives
  • Supplement
  • News
  • AAP Presidential Address
  • ASCI Presidential Address
  • AAP Kober Medal
  • Research Articles
In this issue
In This Issue
/articles/view/120009
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1003-1003. https://doi.org/10.1172/JCI120009.
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In This Issue

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Editorial
Reflecting on 80 years of excellence
Ushma Savla
Ushma Savla
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1006-1016. https://doi.org/10.1172/JCI23290.
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Reflecting on 80 years of excellence

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A small group of members of the American Society for Clinical Investigation began chatting in 1916 about the possibility of launching a new biomedical research journal. By October 1924, they managed to make the idea a reality with the publication of the first issue of the Journal of Clinical Investigation. Our 80th birthday seems an appropriate time to reflect on the history of biomedical science as it has been played out on our pages.

Authors

Ushma Savla

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Historical Highlights
Blasts from the past
Paul A. Insel, … , Stephen J. Weiss, Jean D. Wilson
Paul A. Insel, … , Stephen J. Weiss, Jean D. Wilson
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1017-1033. https://doi.org/10.1172/JCI23321.
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Blasts from the past

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With this issue of the JCI, we celebrate the 80th anniversary of the Journal. While 80 years is not a century, we still feel it is important to honor what the JCI has meant to the biomedical research community for 8 decades. To illustrate why the JCI is the leading general-interest translational research journal edited by and for biomedical researchers, we have asked former JCI editors-in-chief to reflect on some of the major scientific advances reported in the pages of the Journal during their tenures.

Authors

Paul A. Insel, Stuart Kornfeld, Philip W. Majerus, Andrew R. Marks, Paul A. Marks, Arnold S. Relman, Bruce F. Scharschmidt, Thomas P. Stossel, Ajit P. Varki, Stephen J. Weiss, Jean D. Wilson

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Retrospectives
Richard Havel, Howard Eder, and the evolution of lipoprotein analysis
Scott M. Grundy
Scott M. Grundy
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1034-1037. https://doi.org/10.1172/JCI23198.
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Richard Havel, Howard Eder, and the evolution of lipoprotein analysis

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In 1956, the JCI published a paper by Richard Havel, Howard Eder, and Joseph Bragdon on a method using an ultracentrifuge to physically separate plasma lipoproteins and chemical methods to analyze their lipid constituents. This paper has been much cited (7081 times as of this writing) in part because it represents a solid method that, with various modifications, has been applicable for the study of lipoproteins for almost half a century.

Authors

Scott M. Grundy

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Endothelial cell culture: beginnings of modern vascular biology
Ralph L. Nachman, Eric A. Jaffe
Ralph L. Nachman, Eric A. Jaffe
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1037-1040. https://doi.org/10.1172/JCI23284.
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Endothelial cell culture: beginnings of modern vascular biology

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Endothelial cells derived from human umbilical veins were first successfully cultured in vitro in 1973. Weibel-Palade bodies and the von Willebrand factor antigen were used as morphological, immunohistochemical, and functional markers to unequivocally identify the cells. These landmark studies helped initiate the growth of modern vascular biology.

Authors

Ralph L. Nachman, Eric A. Jaffe

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One thing leads to another
Jules Hirsch
Jules Hirsch
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1040-1043. https://doi.org/10.1172/JCI22993.
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One thing leads to another

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In 1956, the JCI published an article by Vincent Dole on a method for titrating plasma fatty acids that uncovered the importance of fatty acids as a substrate for glucose metabolism. When asked to prepare a historical perspective on this very popular paper, I paid Dole a visit and we reminisced. His answer to my question of how he came to do this work on plasma fatty acids was: “Well, one thing leads to another.” Let me remind the reader of what “things” were like in 1956 and how they might have related to Dole’s important contribution.

Authors

Jules Hirsch

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The birth of clinical body plethysmography: it was a good week
John B. West
John B. West
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1043-1045. https://doi.org/10.1172/JCI22992.
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The birth of clinical body plethysmography: it was a good week

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Nearly fifty years ago, Arthur B. DuBois, Julius H. Comroe Jr., and their colleagues published two papers on the use of body plethysmography to measure lung volume and airway resistance. These two articles in the JCI are almost the most-cited doublet in the Journal’s entire archive. Remarkably, the methods described then are still in use today in clinical pulmonary function laboratories. Though body plethysmography had been used before, there were serious technical problems; it was extraordinary that DuBois managed to solve most of these in one week. Times have changed and molecular medicine now dominates the JCI, but these articles remind us that biomedical research goes beyond the molecular.

Authors

John B. West

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Quantifying cerebral blood flow: regional regulation with global implications
Scott A. Small
Scott A. Small
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1046-1048. https://doi.org/10.1172/JCI23159.
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Quantifying cerebral blood flow: regional regulation with global implications

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In 1948, Seymour S. Kety and Carl F. Schmidt published back-to-back papers in the JCI that are widely acknowledged as landmarks. Upon publication, the studies resolved a century-old debate, irrefutably demonstrating that cerebral blood flow is regionally regulated. The reported findings turned out to be so powerful in their implications that they provided the inspirational spark that illuminated a brand-new field: functional brain imaging. Thus these papers are landmarks of the rarest kind, not only ending a controversy, but also giving birth to one of the most exciting fields within modern day neuroscience.

Authors

Scott A. Small

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The legacy of Homer W. Smith: mechanistic insights into renal physiology
L. Gabriel Navar
L. Gabriel Navar
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1048-1050. https://doi.org/10.1172/JCI23150.
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The legacy of Homer W. Smith: mechanistic insights into renal physiology

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In 1945, Homer W. Smith published an article in the JCI that clearly demonstrated that para-aminohippuric acid is the most suitable agent for the evaluation of renal plasma flow in both humans and dogs; in addition, the paper provided detailed methodology that is still in use today. This paper is but one of many outstanding works performed by Smith and his colleagues that clearly established the clearance technique as a powerful noninvasive approach to gain mechanistic insights into intrarenal function.

Authors

L. Gabriel Navar

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Berson, Yalow, and the JCI: the agony and the ecstasy
C. Ronald Kahn, Jesse Roth
C. Ronald Kahn, Jesse Roth
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1051-1054. https://doi.org/10.1172/JCI23316.
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Berson, Yalow, and the JCI: the agony and the ecstasy

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The isolation of insulin in 1921 by Banting, Best, Collip, and Macleod stands as one of the most dramatic stories in modern medical investigation. Only two years passed between the initial experiments in dogs to widespread human application to the awarding of the Nobel Prize in 1923. Insulin-related research has also served as a focus, at least in part, for the work of three other Nobel Prize recipients: determination of the chemical structure of insulin by Frederick Sanger in 1958; determination of the three-dimensional structures of insulin and vitamin B12 by Dorothy Hodgkin in 1964; and finally, the development of immunoassay by Solomon Berson and Rosalyn Yalow in 1959–1960, which led to a Nobel Prize for Yalow in 1977 (five years after the untimely death of Berson). The history of Yalow and Berson’s discovery and its impact on the field is an illustration of the adage that every story has two sides.

Authors

C. Ronald Kahn, Jesse Roth

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Superoxide production by phagocytic leukocytes: the scientific legacy of Bernard Babior
John T. Curnutte
John T. Curnutte
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1054-1057. https://doi.org/10.1172/JCI23377.
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Superoxide production by phagocytic leukocytes: the scientific legacy of Bernard Babior

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It was 32 years ago that Bernard Babior, Ruby Kipnes, and I submitted a paper to the JCI reporting that polymorphonuclear leukocytes produce superoxide (O2–) during phagocytosis and that this highly reactive oxygen radical might function as a microbicidal agent. The story of how our lab came to this discovery is one of a special relationship between a student and his brilliant mentor.

Authors

John T. Curnutte

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Supplement
Acceptance of the Kober Medal It only gets better
K. Frank Austen
K. Frank Austen
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1177-1177. https://doi.org/10.1172/JCI23465.
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Acceptance of the Kober Medal It only gets better

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K. Frank Austen

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News
Group science
Laurie Goodman
Laurie Goodman
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1004-1005. https://doi.org/10.1172/JCI23425.
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Group science

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Authors

Laurie Goodman

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AAP Presidential Address
AAP Presidential Address The AAP and the transformation of medicine
Ralph Snyderman
Ralph Snyderman
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1169-1173. https://doi.org/10.1172/JCI23463.
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AAP Presidential Address The AAP and the transformation of medicine

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Authors

Ralph Snyderman

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ASCI Presidential Address
ASCI Presidential Address Mentoring and teaching clinical investigation
Kenneth Kaushansky
Kenneth Kaushansky
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1165-1168. https://doi.org/10.1172/JCI23462.
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ASCI Presidential Address Mentoring and teaching clinical investigation

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Authors

Kenneth Kaushansky

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AAP Kober Medal
Presentation of the 2004 Kober Medal to K. Frank Austen
Jeffrey M. Drazen
Jeffrey M. Drazen
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1174-1176. https://doi.org/10.1172/JCI23464.
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Presentation of the 2004 Kober Medal to K. Frank Austen

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Authors

Jeffrey M. Drazen

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Research Articles
Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex
Hui-Hua Li, … , Da-Zhi Wang, Cam Patterson
Hui-Hua Li, … , Da-Zhi Wang, Cam Patterson
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1058-1071. https://doi.org/10.1172/JCI22220.
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Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex

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Calcineurin, which binds to the Z-disc in cardiomyocytes via α-actinin, promotes cardiac hypertrophy in response to numerous pathologic stimuli. However, the endogenous mechanisms regulating calcineurin activity in cardiac muscle are not well understood. We demonstrate that a muscle-specific F-box protein called atrogin-1, or muscle atrophy F-box, directly interacts with calcineurin A and α-actinin-2 at the Z-disc of cardiomyocytes. Atrogin-1 associates with Skp1, Cul1, and Roc1 to assemble an SCFatrogin-1 complex with ubiquitin ligase activity. Expression of atrogin-1 decreases levels of calcineurin A and promotes its ubiquitination. Moreover, atrogin-1 attenuates agonist-induced calcineurin activity and represses calcineurin-dependent transactivation and NFATc4 translocation. Conversely, downregulation of atrogin-1 using adenoviral small interfering RNA (siRNA) expression enhances agonist-induced calcineurin activity and cardiomyocyte hypertrophy. Consistent with these cellular observations, overexpression of atrogin-1 in hearts of transgenic mice reduces calcineurin protein levels and blunts cardiac hypertrophy after banding of the thoracic aorta. These studies indicate that the SCFatrogin-1 ubiquitin ligase complex interacts with and represses calcineurin by targeting calcineurin for ubiquitin-mediated proteolysis, leading to inhibition of cardiac hypertrophy in response to pathologic stimuli.

Authors

Hui-Hua Li, Vishram Kedar, Chunlian Zhang, Holly McDonough, Ranjana Arya, Da-Zhi Wang, Cam Patterson

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Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice
Virginie Pétrilli, … , Salvatore Cuzzocrea, Zhao-Qi Wang
Virginie Pétrilli, … , Salvatore Cuzzocrea, Zhao-Qi Wang
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1072-1081. https://doi.org/10.1172/JCI21854.
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Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice

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Poly(ADP-ribosyl)ation is rapidly formed in cells following DNA damage and is regulated by poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is known to be involved in various cellular processes, such as DNA repair, genomic stability, transcription, and cell death. During apoptosis, PARP-1 is cleaved by caspases to generate 89-kDa and 24-kDa fragments, a hallmark of apoptosis. This cleavage is thought to be a regulatory event for cellular death. In order to understand the biological significance of PARP-1 cleavage, we generated a PARP-1 knockin (PARP-1KI/KI) mouse model, in which the caspase cleavage site of PARP-1, DEVD214, was mutated to render the protein resistant to caspases during apoptosis. While PARP-1KI/KI mice developed normally, they were highly resistant to endotoxic shock and to intestinal and renal ischemia-reperfusions, which were associated with reduced inflammatory responses in the target tissues and cells due to the compromised production of specific inflammatory mediators. Despite normal binding of NF-κB to DNA, NF-κB–mediated transcription activity was impaired in the presence of caspase-resistant PARP-1. This study provides a novel insight into the function of PARP-1 in inflammation and ischemia-related pathophysiologies.

Authors

Virginie Pétrilli, Zdenko Herceg, Paul O. Hassa, Nimesh S.A. Patel, Rosanna Di Paola, Ulrich Cortes, Laura Dugo, Helder-Mota Filipe, Christoph Thiemermann, Michael O. Hottiger, Salvatore Cuzzocrea, Zhao-Qi Wang

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Requirement for sphingosine 1–phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference
Sung-Suk Chae, … , Henry Furneaux, Timothy Hla
Sung-Suk Chae, … , Henry Furneaux, Timothy Hla
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1082-1089. https://doi.org/10.1172/JCI22716.
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Requirement for sphingosine 1–phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference

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Angiogenesis, or new blood vessel formation, is critical for the growth and spread of tumors. Multiple phases of this process, namely, migration, proliferation, morphogenesis, and vascular stabilization, are needed for optimal tumor growth beyond a diffusion-limited size. The sphingosine 1–phosphate (S1P) receptor-1 (S1P1) is required for stabilization of nascent blood vessels during embryonic development. Here we show that S1P1 expression is strongly induced in tumor vessels. We developed a multiplex RNA interference technique to downregulate S1P1 in mice. The small interfering RNA (siRNA) for S1P1 specifically silenced the cognate transcript in endothelial cells and inhibited endothelial cell migration in vitro and the growth of neovessels into subcutaneous implants of Matrigel in vivo. Local injection of S1P1 siRNA, but not a negative control siRNA, into established tumors inhibited the expression of S1P1 polypeptide on neovessels while concomitantly suppressing vascular stabilization and angiogenesis, which resulted in dramatic suppression of tumor growth in vivo. These data suggest that S1P1 is a critical component of the tumor angiogenic response and argue for the utility of siRNA technology in antiangiogenic therapeutics.

Authors

Sung-Suk Chae, Ji-Hye Paik, Henry Furneaux, Timothy Hla

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A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice
Eric Marietta, … , Mark R. Pittelkow, Joseph A. Murray
Eric Marietta, … , Mark R. Pittelkow, Joseph A. Murray
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1090-1097. https://doi.org/10.1172/JCI21055.
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A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice

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Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with gluten sensitivity. It presents as a papulovesicular rash and is often associated with enteropathy. The rash resolves when the patient is placed on a gluten-free diet and/or dapsone. DH, as well as celiac disease, is tightly associated with DQ2 and DQ8. A novel mouse model for DH is described that utilizes the NOD background and the HLA-DQ8 transgene. The addition of DQ8 contributes sensitivity to gliadin, and the addition of the NOD background contributes to autoimmunity and pathogenesis. Fifteen NOD DQ8+ mice of 90 that were sensitized to gluten developed blistering pathology similar to that seen in DH. Neutrophil infiltration of the dermis, deposition of IgA at the dermal-epidermal junction, and a complete reversal of the blistering phenomenon with the administration of a gluten-free diet with or without dapsone were observed. None of the 3 blistering mice examined had small-bowel pathology. This animal model of DH will be useful to determine the specificity of the IgA deposits, as well as the pathogenic mechanisms that occur in the skin as a result of gluten ingestion.

Authors

Eric Marietta, Kay Black, Michael Camilleri, Patricia Krause, Roy S. Rogers III, Chella David, Mark R. Pittelkow, Joseph A. Murray

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Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis
Jörn Karhausen, … , Sean P. Colgan, Volker H. Haase
Jörn Karhausen, … , Sean P. Colgan, Volker H. Haase
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1098-1106. https://doi.org/10.1172/JCI21086.
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Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis

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Mucosal epithelial cells are uniquely equipped to maintain barrier function even under adverse conditions. Previous studies have implicated hypoxia in mucosal tissue damage resulting from both acute and chronic inflammation. Given the importance of the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) for adaptive hypoxia responses, we hypothesized that HIF-1 may serve as a barrier-protective element during mucosal inflammation. Initial studies of hapten-based murine colitis revealed extensive mucosal hypoxia and concomitant HIF-1 activation during colitis. To study this in more detail, we generated 2 mouse lines with intestinal epithelium–targeted expression of either mutant Hif1a (inability to form HIF-1) or mutant von Hippel-Lindau gene (Vhlh; constitutively active HIF-1). Studies of colitis in these mice revealed that decreased HIF-1 expression correlated with more severe clinical symptoms (mortality, weight loss, colon length), while increased HIF levels were protective in these parameters. Furthermore, colons with constitutive activation of HIF displayed increased expression levels of HIF-1–regulated barrier-protective genes (multidrug resistance gene-1, intestinal trefoil factor, CD73), resulting in attenuated loss of barrier during colitis in vivo. Taken together, these studies provide insight into tissue microenvironmental changes during model inflammatory bowel disease and identify HIF-1 as a critical factor for barrier protection during mucosal insult.

Authors

Jörn Karhausen, Glenn T. Furuta, John E. Tomaszewski, Randall S. Johnson, Sean P. Colgan, Volker H. Haase

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Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics
Mona D. Lee, … , Francis M. Sirotnak, David A. Scheinberg
Mona D. Lee, … , Francis M. Sirotnak, David A. Scheinberg
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1107-1116. https://doi.org/10.1172/JCI22269.
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Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics

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Peptide deformylase activity was thought to be limited to ribosomal protein synthesis in prokaryotes, where new peptides are initiated with an N-formylated methionine. We describe here a new human peptide deformylase (Homo sapiens PDF, or HsPDF) that is localized to the mitochondria. HsPDF is capable of removing formyl groups from N-terminal methionines of newly synthesized mitochondrial proteins, an activity previously not thought to be necessary in mammalian cells. We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines. We designed and synthesized 33 chemical analogs of actinonin; all of the molecules with potent activity against HsPDF also inhibited tumor cell growth, and vice versa, confirming target specificity. Small interfering RNA inhibition of HsPDF protein expression was also antiproliferative. Actinonin treatment of cells led to a tumor-specific mitochondrial membrane depolarization and ATP depletion in a time- and dose-dependent manner; removal of actinonin led to a recovery of the membrane potential consistent with indirect effects on the electron transport chain. In animal models, oral or parenteral actinonin was well tolerated and inhibited human prostate cancer and lung cancer growth. We conclude that HsPDF is a new human mitochondrial enzyme that may provide a novel selective target for anticancer therapy by use of actinonin-based antibiotics.

Authors

Mona D. Lee, Yuhong She, Michael J. Soskis, Christopher P. Borella, Jeffrey R. Gardner, Paula A. Hayes, Benzon M. Dy, Mark L. Heaney, Mark R. Philips, William G. Bornmann, Francis M. Sirotnak, David A. Scheinberg

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Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis
Takehiko Dohi, … , Janet Plescia, Dario C. Altieri
Takehiko Dohi, … , Janet Plescia, Dario C. Altieri
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1117-1127. https://doi.org/10.1172/JCI22222.
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Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis

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Evasion of apoptosis is a hallmark of cancer, but the molecular circuitries of this process are not understood. Here we show that survivin, a member of the inhibitor of apoptosis gene family that is overexpressed in cancer, exists in a novel mitochondrial pool in tumor cells. In response to cell death stimulation, mitochondrial survivin is rapidly discharged in the cytosol, where it prevents caspase activation and inhibits apoptosis. Selective targeting of survivin to mitochondria enhances colony formation in soft agar, accelerates tumor growth in immunocompromised animals, and abolishes tumor cell apoptosis in vivo. Therefore, mitochondrial survivin orchestrates a novel pathway of apoptosis inhibition, which contributes to tumor progression.

Authors

Takehiko Dohi, Elena Beltrami, Nathan R. Wall, Janet Plescia, Dario C. Altieri

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Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin
Atsuhiro Ichihara, … , Tadashi Inagami, Takao Saruta
Atsuhiro Ichihara, … , Tadashi Inagami, Takao Saruta
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1128-1135. https://doi.org/10.1172/JCI21398.
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Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin

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We found that when a site-specific binding protein interacts with the “handle” region of the prorenin prosegment, the prorenin molecule undergoes a conformational change to its enzymatically active state. This nonproteolytic activation is completely blocked by a decoy peptide with the handle region structure, which competitively binds to such a binding protein. Given increased plasma prorenin in diabetes, we examined the hypothesis that the nonproteolytic activation of prorenin plays a significant role in diabetic organ damage. Streptozotocin-induced diabetic rats were treated with subcutaneous administration of handle region peptide. Metabolic and renal histological changes and the renin-Ang system components in the plasma and kidneys were determined at 8, 16, and 24 weeks following streptozotocin treatment. Kidneys of diabetic rats contained increased Ang I and II without any changes in renin, Ang-converting enzyme, or angiotensinogen synthesis. Treatment with the handle region peptide decreased the renal content of Ang I and II, however, and completely inhibited the development of diabetic nephropathy without affecting hyperglycemia. We propose that the nonproteolytic activation of prorenin may be a significant mechanism of diabetic nephropathy. The mechanism and substances causing nonproteolytic activation of prorenin may serve as important therapeutic targets for the prevention of diabetic organ damage.

Authors

Atsuhiro Ichihara, Matsuhiko Hayashi, Yuki Kaneshiro, Fumiaki Suzuki, Tsutomu Nakagawa, Yuko Tada, Yukako Koura, Akira Nishiyama, Hirokazu Okada, M. Nasir Uddin, A.H.M. Nurun Nabi, Yuichi Ishida, Tadashi Inagami, Takao Saruta

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Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice
Dhananjay K. Kaul, … , Ronald L. Nagel, Mary E. Fabry
Dhananjay K. Kaul, … , Ronald L. Nagel, Mary E. Fabry
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1136-1145. https://doi.org/10.1172/JCI21633.
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Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice

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In sickle cell disease, intravascular sickling and attendant flow abnormalities underlie the chronic inflammation and vascular endothelial abnormalities. However, the relationship between sickling and vascular tone is not well understood. We hypothesized that sickling-induced vaso-occlusive events and attendant oxidative stress will affect microvascular regulatory mechanisms. In the present studies, we have examined whether microvascular abnormalities expressed in sickle transgenic-knockout Berkeley (BERK) mice (which express exclusively human α- and βS-globins with <1% γ-globin levels) are amenable to correction with increased levels of antisickling fetal hemoglobin (HbF). In BERK mice, sickling, increased oxidative stress, and hemolytic anemia are accompanied by vasodilation, compensatory increases in eNOS and COX-2, and attenuated vascular responses to NO-mediated vasoactive stimuli and norepinephrine. The hypotension and vasodilation (required for adequate oxygen delivery in the face of chronic anemia) are mediated by non-NO vasodilators (i.e., prostacyclin) as evidenced by induction of COX-2. In BERK mice, the resistance to NO-mediated vasodilators is associated with increased oxidative stress and hemolytic rate, and in BERK + γ mice (expressing 20% HbF), an improved response to these stimuli is associated with reduced oxidative stress and hemolytic rate. Furthermore, BERK + γ mice show normalization of vessel diameters, and eNOS and COX-2 expression. These results demonstrate a strong relationship between sickling and microvascular function in sickle cell disease.

Authors

Dhananjay K. Kaul, Xiao-du Liu, Hee-Yoon Chang, Ronald L. Nagel, Mary E. Fabry

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Epigenetic regulation of 11β-hydroxysteroid dehydrogenase type 2 expression
Rasoul Alikhani-Koopaei, … , Felix J. Frey, Brigitte M. Frey
Rasoul Alikhani-Koopaei, … , Felix J. Frey, Brigitte M. Frey
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1146-1157. https://doi.org/10.1172/JCI21647.
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Epigenetic regulation of 11β-hydroxysteroid dehydrogenase type 2 expression

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Abstract

The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) is selectively expressed in aldosterone target tissues, where it confers aldosterone selectivity for the mineralocorticoid receptor by inactivating 11β-hydroxyglucocorticoids. Variable activity of 11βHSD2 is relevant for blood pressure control and hypertension. The present investigation aimed to elucidate whether an epigenetic mechanism, DNA methylation, accounts for the rigorous control of expression of the gene encoding 11βHSD2, HSD11B2. CpG islands covering the promoter and exon 1 of HSD11B2 were found to be densely methylated in tissues and cell lines with low expression but not those with high expression of HSD11B2. Demethylation induced by 5-aza-2′-deoxycytidine and procainamide enhanced the transcription and activity of the 11βHSD2 enzyme in human cells in vitro and in rats in vivo. Methylation of HSD11B2 promoter–luciferase constructs decreased transcriptional activity. Methylation of recognition sequences of transcription factors, including those for Sp1/Sp3, Arnt, and nuclear factor 1 (NF1) diminished their DNA-binding activity. Herein NF1 was identified as a strong HSD11B2 stimulatory factor. The effect of NF1 was dependent on the position of CpGs and the combination of CpGs methylated. A methylated-CpG–binding protein complex 1 transcriptional repression interacted directly with the methylated HSD11B2 promoter. These results indicate a role for DNA methylation in HSD11B2 gene repression and suggest an epigenetic mechanism affecting this gene causally linked with hypertension.

Authors

Rasoul Alikhani-Koopaei, Fatemeh Fouladkou, Felix J. Frey, Brigitte M. Frey

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Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans
Supriya Srinivasan, … , Bruce R. Conklin, Christian Vaisse
Supriya Srinivasan, … , Bruce R. Conklin, Christian Vaisse
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1158-1164. https://doi.org/10.1172/JCI21927.
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Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans

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Abstract

The melanocortin-4 receptor (MC4R), a centrally expressed G protein–coupled receptor (GPCR), is essential for the maintenance of long-term energy balance in humans. Mutations in MC4R are the most common genetic cause of obesity. Since activation of this receptor leads to a decrease in food intake, MC4R is also a major therapeutic target for the treatment of obesity. Control of MC4R activity in vivo is modulated by the opposing effects of the anorexigenic agonist α–melanocyte-stimulating hormone (α-MSH) and the orexigenic antagonist agouti-related protein (AGRP). In addition, experiments in vitro have demonstrated that the human MC4R has an intrinsic constitutive activity on which AGRP also acts as an inverse agonist. The physiological role of this constitutive activity in the control of energy balance as well as the domain of the protein implicated in its maintenance are unknown. By systematically studying functional defects in naturally occurring MC4R mutations from obese patients, we defined a cluster of N-terminal mutations that selectively impair the constitutive activity of the receptor. Further characterization of this domain demonstrated that it functions as a tethered intramolecular ligand that maintains the constitutive activity of MC4R and may provide novel avenues for the design of drugs targeting this receptor. Our results also suggest that the tonic satiety signal provided by the constitutive activity of MC4R may be required for maintaining long-term energy homeostasis in humans.

Authors

Supriya Srinivasan, Cecile Lubrano-Berthelier, Cedric Govaerts, Franck Picard, Pamela Santiago, Bruce R. Conklin, Christian Vaisse

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