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A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.
Journal article

A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

  • Doyle JJ Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Doyle AJ Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Wilson NK Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Habashi JP Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Bedja D Department of Cardiology, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Whitworth RE Research Triangle Institute International, Durham, United States.
  • Lindsay ME Thoracic Aortic Center, Departments of Medicine and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
  • Schoenhoff F Department of Cardiovascular Surgery, Inselspital, Bern, Switzerland.
  • Myers L Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Huso N Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Bachir S Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Squires O Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Rusholme B Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Ehsan H Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Huso D Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Thomas CJ Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, United States.
  • Caulfield MJ William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
  • Van Eyk JE Proteomics Innovation Center in Heart Failure, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Judge DP Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Dietz HC Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
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  • 2015-10-28
Published in:
  • eLife. - 2015
Amlodipine
ERK
Hydralazine
Marfan syndrome
TGF-β signaling
Verapamil
aortic aneurysm
calcium channel blocker
chromosomes
genes
human
human biology
medicine
mouse
protein kinase C
Adult
Animals
Antihypertensive Agents
Calcium Channel Blockers
Child
Child, Preschool
Disease Models, Animal
Humans
Hydralazine
Indoles
Longitudinal Studies
MAP Kinase Signaling System
Marfan Syndrome
Mice, Inbred C57BL
Protein Kinase C beta
Receptor, Angiotensin, Type 1
Survival Analysis
Treatment Outcome
English Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/201310
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