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

Jefferson J. Doyle, Alexander J. Doyle, Nicole K. Wilson, Jennifer P. Habashi, Djahida Bedja, Ryan E. Whitworth, Mark E. Lindsay, Florian Schoenhoff, Loretha Myers, Nick Huso, Suha Bachir, Oliver Squires, Benjamin Rusholme, Hamid Ehsan, David Huso, Craig J. Thomas, Mark J. Caulfield, Jennifer E. Van Eyk, Daniel P. Judge, Harry C. DietzCarrie Farrar, Williams Ravekes, Harry C. Dietz, Kira Lurman, Kathryn W. Holmes, Jennifer Habashi, Dianna M. Milewicz, Siddharth K. Prakash, Meghan Terry, Scott A. Lemaire, Shaine A. Morris, Irina Volguina, Cheryl L. Maslen, Howard K. Song, G. Michael Silberbach, Reed E. Pyeritz, Joseph E. Bavaria, Karianna Milewski, Amber Parker, Richard B. Devereux, Jonathan W. Weinsaft, Mary J. Roman, Tanya Latortue, Ralph Shohet, Fionna Kennedy, Nazli McDonnell, Ben Griswold, Federico M. Asch, Neil J. Weissman, Kim A. Eagle, H. Eser Tolunay, Patrice Desvigne-Nickens, Mario P. Stylianou, Megan Mitchell, Hung Tseng, Barbara L. Kroner, Tabitha Hendershot, Ryan Whitworth, Danny Ringer, Harry C. Dietz, Andy McCallion, Bart Loeys, Lut Van Laer, Per Eriksson, Anders Franco-Cereceda, Luc Mertens, Seema Mittal, Salah A. Mohamed, Gregor Andelfinger, Harry C. Dietz

Research output: Contribution to journalArticle

38 Scopus citations

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.

Original languageEnglish (US)
Article numbere08648
JournaleLife
Volume4
Issue numberOCTOBER2015
DOIs
StatePublished - Oct 27 2015

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    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. (2015). A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. eLife, 4(OCTOBER2015), [e08648]. https://doi.org/10.7554/eLife.08648