Doyle, Jefferson JJefferson JDoyleDoyle, Alexander JAlexander JDoyleWilson, Nicole KNicole KWilsonHabashi, Jennifer PJennifer PHabashiBedja, DjahidaDjahidaBedjaWhitworth, Ryan ERyan EWhitworthLindsay, Mark EMark ELindsaySchönhoff, FlorianFlorianSchönhoffMyers, LorethaLorethaMyersHuso, NickNickHusoBachir, SuhaSuhaBachirSquires, OliverOliverSquiresRusholme, BenjaminBenjaminRusholmeEhsan, HamidHamidEhsanHuso, DavidDavidHusoThomas, Craig JCraig JThomasCaulfield, Mark JMark JCaulfieldVan Eyk, Jennifer EJennifer EVan EykJudge, Daniel PDaniel PJudgeDietz, Harry CHarry CDietz2024-10-232024-10-232015https://boris-portal.unibe.ch/handle/20.500.12422/137277Calcium 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.enAmlodipineERKHydralazineMarfan syndromeTGF-β signalingVerapamilaortic aneurysmcalcium channel blockerchromosomesgeneshumanhuman biologymedicinemouseprotein kinase C600 - Technology::610 - Medicine & healtharticle10.7892/boris.748872650606410.7554/eLife.08648