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; Carrie 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

doi:10.7554/eLife.08648

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

^*Corresponding author for this work

Faculty of Medicine, Health and Human Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	e08648
Pages (from-to)	1-18
Number of pages	18
Journal	eLife
Volume	4
Issue number	OCTOBER2015
DOIs	https://doi.org/10.7554/eLife.08648
Publication status	Published - 27 Oct 2015

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Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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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), 1-18. Article e08648. https://doi.org/10.7554/eLife.08648

@article{d96b26ecea274e97af35796f1adf19a2,

title = "A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome",

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.",

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

note = "Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2015",

month = oct,

day = "27",

doi = "10.7554/eLife.08648",

language = "English",

volume = "4",

pages = "1--18",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

number = "OCTOBER2015",

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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, KW, Habashi, J, Milewicz, DM, Prakash, SK, Terry, M, Lemaire, SA, Morris, SA, Volguina, I, Maslen, CL, Song, HK, 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, pp. 1-18. https://doi.org/10.7554/eLife.08648

TY - JOUR

T1 - A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome

AU - Doyle, Jefferson J.

AU - Doyle, Alexander J.

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 W.

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 L.

AU - Song, Howard K.

AU - Silberbach, G. 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

AU - Tseng, Hung

AU - Kroner, Barbara L.

AU - Hendershot, Tabitha

AU - Whitworth, Ryan

AU - Ringer, Danny

AU - Dietz, Harry C.

AU - McCallion, Andy

AU - Loeys, Bart

AU - Van Laer, Lut

AU - Eriksson, Per

AU - Franco-Cereceda, Anders

AU - Mertens, Luc

AU - Mittal, Seema

AU - Mohamed, Salah A.

AU - Andelfinger, Gregor

AU - Dietz, Harry C.

N1 - Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2015/10/27

Y1 - 2015/10/27

N2 - 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.

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.

UR - https://www.scopus.com/pages/publications/84946605554

U2 - 10.7554/eLife.08648

DO - 10.7554/eLife.08648

M3 - Article

C2 - 26506064

AN - SCOPUS:84946605554

SN - 2050-084X

VL - 4

SP - 1

EP - 18

JO - eLife

JF - eLife

IS - OCTOBER2015

M1 - e08648

ER -

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

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