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

作者：Doyle Jefferson J; Doyle Alexander J; Wilson Nicole K; Habashi Jennifer P; Bedja Djahida; Whitworth Ryan E; Lindsay Mark E; Schoenhoff 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; Dietz Harry C

来源：eLife, 2015, 4: e08648.

DOI：10.7554/eLife.08648

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 (PKC beta) as a critical mediator of this pathway and demonstrate that the PKC beta inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCa 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.

• 出版日期2015-10-27
• 单位河北医科大学