A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.
Publication year
2015Source
Elife, 4, (2015), article e08648ISSN
Publication type
Article / Letter to editor

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Organization
Human Genetics
Journal title
Elife
Volume
vol. 4
Subject
Radboudumc 0: Other Research RIMLS: Radboud Institute for Molecular Life SciencesAbstract
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 (PKCbeta) as a critical mediator of this pathway and demonstrate that the PKCbeta inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCbeta 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.
This item appears in the following Collection(s)
- Academic publications [202786]
- Electronic publications [100861]
- Faculty of Medical Sciences [80017]
- Open Access publications [69577]
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