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Title: A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.
Author(s): Doyle, J.J.; Doyle, A.J.; Wilson, N.K.; Habashi, J.P.; Bedja, D.; Whitworth, R.E.; Lindsay, M.E.; Schoenhoff, F.; Myers, L.; Huso, N.; Bachir, S.; Squires, O.; Rusholme, B.; Ehsan, H.; Huso, D.; Thomas, C.J.; Caulfield, M.J.; Eyk, J.E. Van; Judge, D.P.; Dietz, H.C.; Loeys, B.L. ; et al.
Publication year: 2015
Source: Elife, vol. 4, (2015), article e08648
ISSN: 2050-084X
DOI: https://doi.org/10.7554/eLife.08648
Publication type: Article / Letter to editor

Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/156874   https://hdl.handle.net/2066/156874

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Subject: Radboudumc 0: Other Research RIMLS: Radboud Institute for Molecular Life Sciences
Organization: Human Genetics
Journal title:
Elife
Volume: vol. 4
Article number: e08648
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 (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.

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