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

Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K; Habashi, Jennifer P; Bedja, Djahida; Whitworth, Ryan E; Lindsay, Mark E; Schönhoff, Florian; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Ehsan, Hamid; Huso, David; Thomas, Craig J; Caulfield, Mark J; Van Eyk, Jennifer E; Judge, Daniel P and Dietz, Harry C (2015). A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. eLife, 4 eLife Sciences Publications 10.7554/eLife.08648

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiovascular Surgery

UniBE Contributor:

Schönhoff, Florian

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2050-084X

Publisher:

eLife Sciences Publications

Language:

English

Submitter:

Daniela Huber

Date Deposited:

02 Feb 2016 16:30

Last Modified:

02 Feb 2016 16:30

Publisher DOI:

10.7554/eLife.08648

PubMed ID:

26506064

Uncontrolled 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

BORIS DOI:

10.7892/boris.74887

URI:

https://boris.unibe.ch/id/eprint/74887

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