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. Dietz & 50 others Carrie Farrar, Williams Ravekes, Harry C. Dietz, Kira Lurman, Kathryn Holmes, Jennifer Habashi, Dianna M. Milewicz, Siddharth K. Prakash, Meghan Terry, Scott A. Lemaire, Shaine A. Morris, Irina Volguina, Cheryl Maslen, Howard Song, Gary (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

32 Citations (Scopus)

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

Fingerprint

Protein Kinase C beta
Gene-Environment Interaction
Marfan Syndrome
Calcium Channel Blockers
Genes
Antihypertensive Agents
Thoracic Aortic Aneurysm
Dissection
Hydralazine
Angiotensin Type 1 Receptor
Critical Pathways
Aortic Aneurysm
Mitogen-Activated Protein Kinase 1
Extracellular Signal-Regulated MAP Kinases
Surgery
Aneurysm
Rupture
Chemical activation
Display devices
Association reactions

ASJC Scopus subject areas

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

Cite this

Doyle, J. J., Doyle, A. J., Wilson, N. K., Habashi, J. P., Bedja, D., Whitworth, R. E., ... 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

A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. / 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.; Farrar, Carrie; Ravekes, Williams; Dietz, Harry C.; Lurman, Kira; Holmes, Kathryn; Habashi, Jennifer; Milewicz, Dianna M.; Prakash, Siddharth K.; Terry, Meghan; Lemaire, Scott A.; Morris, Shaine A.; Volguina, Irina; Maslen, Cheryl; Song, Howard; Silberbach, Gary (Michael); Pyeritz, Reed E.; Bavaria, Joseph E.; Milewski, Karianna; Parker, Amber; Devereux, Richard B.; Weinsaft, Jonathan W.; Roman, Mary J.; Latortue, Tanya; Shohet, Ralph; Kennedy, Fionna; McDonnell, Nazli; Griswold, Ben; Asch, Federico M.; Weissman, Neil J.; Eagle, Kim A.; Tolunay, H. Eser; Desvigne-Nickens, Patrice; Stylianou, Mario P.; Mitchell, Megan; Tseng, Hung; Kroner, Barbara L.; Hendershot, Tabitha; Whitworth, Ryan; Ringer, Danny; Dietz, Harry C.; McCallion, Andy; Loeys, Bart; Van Laer, Lut; Eriksson, Per; Franco-Cereceda, Anders; Mertens, Luc; Mittal, Seema; Mohamed, Salah A.; Andelfinger, Gregor; Dietz, Harry C.

In: eLife, Vol. 4, No. OCTOBER2015, e08648, 27.10.2015.

Research output: Contribution to journalArticle

Doyle, JJ, Doyle, AJ, Wilson, NK, Habashi, JP, Bedja, D, Whitworth, RE, Lindsay, ME, Schoenhoff, F, Myers, L, Huso, N, Bachir, S, Squires, O, Rusholme, B, Ehsan, H, Huso, D, Thomas, CJ, Caulfield, MJ, Van Eyk, JE, Judge, DP, Dietz, HC, Farrar, C, Ravekes, W, Dietz, HC, Lurman, K, Holmes, K, Habashi, J, Milewicz, DM, Prakash, SK, Terry, M, Lemaire, SA, Morris, SA, Volguina, I, Maslen, C, Song, H, Silberbach, GM, Pyeritz, RE, Bavaria, JE, Milewski, K, Parker, A, Devereux, RB, Weinsaft, JW, Roman, MJ, Latortue, T, Shohet, R, Kennedy, F, McDonnell, N, Griswold, B, Asch, FM, Weissman, NJ, Eagle, KA, Tolunay, HE, Desvigne-Nickens, P, Stylianou, MP, Mitchell, M, Tseng, H, Kroner, BL, Hendershot, T, Whitworth, R, Ringer, D, Dietz, HC, McCallion, A, Loeys, B, Van Laer, L, Eriksson, P, Franco-Cereceda, A, Mertens, L, Mittal, S, Mohamed, SA, Andelfinger, G & Dietz, HC 2015, 'A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome', eLife, vol. 4, no. OCTOBER2015, e08648. https://doi.org/10.7554/eLife.08648
Doyle JJ, Doyle AJ, Wilson NK, Habashi JP, Bedja D, Whitworth RE et al. A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. eLife. 2015 Oct 27;4(OCTOBER2015). e08648. https://doi.org/10.7554/eLife.08648
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. ; Farrar, Carrie ; Ravekes, Williams ; Dietz, Harry C. ; Lurman, Kira ; Holmes, Kathryn ; Habashi, Jennifer ; Milewicz, Dianna M. ; Prakash, Siddharth K. ; Terry, Meghan ; Lemaire, Scott A. ; Morris, Shaine A. ; Volguina, Irina ; Maslen, Cheryl ; Song, Howard ; Silberbach, Gary (Michael) ; Pyeritz, Reed E. ; Bavaria, Joseph E. ; Milewski, Karianna ; Parker, Amber ; Devereux, Richard B. ; Weinsaft, Jonathan W. ; Roman, Mary J. ; Latortue, Tanya ; Shohet, Ralph ; Kennedy, Fionna ; McDonnell, Nazli ; Griswold, Ben ; Asch, Federico M. ; Weissman, Neil J. ; Eagle, Kim A. ; Tolunay, H. Eser ; Desvigne-Nickens, Patrice ; Stylianou, Mario P. ; Mitchell, Megan ; Tseng, Hung ; Kroner, Barbara L. ; Hendershot, Tabitha ; Whitworth, Ryan ; Ringer, Danny ; Dietz, Harry C. ; McCallion, Andy ; Loeys, Bart ; Van Laer, Lut ; Eriksson, Per ; Franco-Cereceda, Anders ; Mertens, Luc ; Mittal, Seema ; Mohamed, Salah A. ; Andelfinger, Gregor ; Dietz, Harry C. / A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. In: eLife. 2015 ; Vol. 4, No. OCTOBER2015.
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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.",
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AU - Wilson, Nicole K.

AU - Habashi, Jennifer P.

AU - Bedja, Djahida

AU - Whitworth, Ryan E.

AU - Lindsay, Mark E.

AU - Schoenhoff, Florian

AU - Myers, Loretha

AU - Huso, Nick

AU - Bachir, Suha

AU - Squires, Oliver

AU - Rusholme, Benjamin

AU - Ehsan, Hamid

AU - Huso, David

AU - Thomas, Craig J.

AU - Caulfield, Mark J.

AU - Van Eyk, Jennifer E.

AU - Judge, Daniel P.

AU - Dietz, Harry C.

AU - Farrar, Carrie

AU - Ravekes, Williams

AU - Dietz, Harry C.

AU - Lurman, Kira

AU - Holmes, Kathryn

AU - Habashi, Jennifer

AU - Milewicz, Dianna M.

AU - Prakash, Siddharth K.

AU - Terry, Meghan

AU - Lemaire, Scott A.

AU - Morris, Shaine A.

AU - Volguina, Irina

AU - Maslen, Cheryl

AU - Song, Howard

AU - Silberbach, Gary (Michael)

AU - Pyeritz, Reed E.

AU - Bavaria, Joseph E.

AU - Milewski, Karianna

AU - Parker, Amber

AU - Devereux, Richard B.

AU - Weinsaft, Jonathan W.

AU - Roman, Mary J.

AU - Latortue, Tanya

AU - Shohet, Ralph

AU - Kennedy, Fionna

AU - McDonnell, Nazli

AU - Griswold, Ben

AU - Asch, Federico M.

AU - Weissman, Neil J.

AU - Eagle, Kim A.

AU - Tolunay, H. Eser

AU - Desvigne-Nickens, Patrice

AU - Stylianou, Mario P.

AU - Mitchell, Megan

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AU - Van Laer, Lut

AU - Eriksson, Per

AU - Franco-Cereceda, Anders

AU - Mertens, Luc

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AU - Mohamed, Salah A.

AU - Andelfinger, Gregor

AU - Dietz, Harry C.

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AB - 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.

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