A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.
Publication/Presentation Date
10-27-2015
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.
Volume
4
ISSN
2050-084X
Published In/Presented At
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., Van Eyk, J. E., Judge, D. P., Dietz, H. C., … MIBAVA Leducq Consortium (2015). A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. eLife, 4, e08648. https://doi.org/10.7554/eLife.08648
Disciplines
Medicine and Health Sciences
PubMedID
26506064
Department(s)
Department of Surgery
Document Type
Article