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Elife. 2015 Oct 27;4. pii: e08648. doi: 10.7554/eLife.08648.

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

Author information

1
Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.
2
Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United States.
3
William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
4
Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, United States.
5
Department of Cardiology, Johns Hopkins University School of Medicine, Baltimore, United States.
6
Australian School of Advanced Medicine, Macquarie University, Sydney, Australia.
7
Research Triangle Institute International, Durham, United States.
8
Thoracic Aortic Center, Departments of Medicine and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
9
Department of Cardiovascular Surgery, Inselspital, Bern, Switzerland.
10
Proteomics Innovation Center in Heart Failure, Johns Hopkins University School of Medicine, Baltimore, United States.
11
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, United States.
12
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, United States.
13
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.

Abstract

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.

KEYWORDS:

Amlodipine; ERK; Hydralazine; Marfan syndrome; TGF-β signaling; Verapamil; aortic aneurysm; calcium channel blocker; chromosomes; genes; human; human biology; medicine; mouse; protein kinase C

PMID:
26506064
PMCID:
PMC4621743
DOI:
10.7554/eLife.08648
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

HCD: Reviewing editor, eLife. The other authors declare that no competing interests exist.

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