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, GenTAC Registry Consortium, MIBAVA Leducq Consortium, 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, Liliana Preiss, Meg Cunningham, Natalia Bradley, Harry C Dietz, Andrew S McCallion, Bart Loeys, Lut Van Laer, Per Eriksson, Anders Franco-Cereceda, Luc Mertens, Seema Mittal, Salah A Mohamed, Gregor Andelfinger, 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, GenTAC Registry Consortium, MIBAVA Leducq Consortium, 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, Liliana Preiss, Meg Cunningham, Natalia Bradley, Harry C Dietz, Andrew S McCallion, Bart Loeys, Lut Van Laer, Per Eriksson, Anders Franco-Cereceda, Luc Mertens, Seema Mittal, Salah A Mohamed, Gregor Andelfinger

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.

Keywords: Amlodipine; ERK; Hydralazine; Marfan syndrome; TGF-β signaling; Verapamil; aortic aneurysm; calcium channel blocker; chromosomes; genes; human; human biology; medicine; mouse; protein kinase C.

Conflict of interest statement

HCD: Reviewing editor, eLife. The other authors declare that no competing interests exist.

Figures

Figure 1.. Effect of amlodipine in wild-type…
Figure 1.. Effect of amlodipine in wild-type (WT) and Marfan mice.
(A) Echocardiography data showing mean (±2 SEM) growth in the aortic root and ascending aorta from 2 to 4 months of age. Number of mice per group (male/female) = WT placebo 11 (5/6), WT amlodipine 10 (6/4), Marfan placebo 14 (7/7), Marfan amlodipine 11 (6/5). Mean (±2 SEM) weight per group (in grams) at 4 months = 27.4 ± 2.4 g (WT placebo), 27.6 ± 2.8 g (WT amlodipine), 28.1 ± 3.0 g (Marfan placebo), 27.9 ± 2.8 g (Marfan amlodipine). (B) Survival curve from 2 to 5 months of age. Number of mice per group (male/female) = WT placebo 11 (5/6), WT amlodipine 10 (6/4), Marfan placebo 14 (7/7), Marfan amlodipine 19 (9/10). (C) Representative VVG staining (upper panel) and Masson's trichrome staining (lower panel) of the proximal ascending aorta in 5-month-old male mice. Scale bar: 40 µm. (D) Mean (±2 SEM) aortic wall architecture score of the proximal ascending aorta in 5-month-old mice. Number of mice per group = 4 (2 male, 2 female). Scale: 1 (normal) to 5 (extensive damage). Plac, placebo; Aml, amlodipine. DOI:http://dx.doi.org/10.7554/eLife.08648.003
Figure 1—figure supplement 1.. Effect of amlodipine…
Figure 1—figure supplement 1.. Effect of amlodipine in wild-type (WT) and Marfan mice.
(S1) Mean (±2 SEM) systolic and diastolic blood pressure, and heart rate, in 3-month-old mice. Number of mice per group = 8 (4 male; 4 female). (S2) Representative latex-injected images showing ascending aortic size (distance between arrowheads) in 5-month-old male mice. Scale bar: 2 mm. (S3) Representative VVG staining (upper panel) and Masson's trichrome staining (lower panel) of the descending thoracic aorta in 5-month-old male mice. Scale bar: 40 µm. (S4) Mean (±2 SEM) aortic wall architecture score of the descending thoracic aorta in 5-month-old mice. Number of mice per group = 4 (2 male, 2 female). Scale: 1 (normal) to 5 (extensive damage). (S5) Mean (±2 SEM) aortic root and ascending aortic growth from 2 to 4 months of age in mice treated with 3 mg/kg/day amlodipine. Number of mice per group (male/female) = WT placebo 5 (3/2), WT amlodipine 5 (2/3), Marfan placebo 10 (6/4), Marfan amlodipine 8 (4/4). Plac, placebo; Los, losartan; Aml, amlodipine. DOI:http://dx.doi.org/10.7554/eLife.08648.004
Figure 2.. Effect of verapamil in wild-type…
Figure 2.. Effect of verapamil in wild-type (WT) and Marfan mice.
(A) Mean (±2 SEM) growth in the aortic root and ascending aorta from 2 to 6 months of age. Number of mice per group (male/female) = WT placebo 8 (4/4), WT verapamil 10 (4/6), Marfan placebo 9 (5/4), Marfan verapamil 11 (6/5). Mean (±2 SEM) weight per group (in grams) at 6 months = 30.3 ± 2.6 g (WT placebo), 30.6 ± 2.2 g (WT verapamil), 31.3 ± 3.3 g (Marfan placebo), 31.5 ± 3.2 g (Marfan verapamil). (B) Representative VVG staining (upper panel) and Masson's trichrome staining (lower panel) of the proximal ascending aorta in 6-month-old male mice. Scale bar: 40 µm. (C) Mean (±2 SEM) aortic wall architecture score of the proximal ascending aorta in 6-month-old mice. Number of mice per group = 4 (2 male, 2 female). Scale: 1 (normal) to 5 (extensive damage). Plac, placebo; Ver, verapamil. DOI:http://dx.doi.org/10.7554/eLife.08648.005
Figure 2—figure supplement 1.. Effect of verapamil…
Figure 2—figure supplement 1.. Effect of verapamil in wild-type (WT) and Marfan mice.
(S1) Representative latex-injected images showing aortic size (distance between arrowheads) in 6-month-old male mice. Scale bar: 2 mm. (S2) Representative VVG staining (upper panel) and Masson's trichrome staining (lower panel) of the descending thoracic aorta in 6-month-old male mice. Scale bar: 40 µm. (S3) Mean (±2 SEM) aortic wall architecture score of the descending thoracic aorta in 6-month-old mice. Number of mice per group = 4 (2 male, 2 female). Scale: 1 (normal) to 5 (extensive damage). Plac, placebo; Ver, verapamil. DOI:http://dx.doi.org/10.7554/eLife.08648.006
Figure 3.. CCB effect is ERK1/2- and…
Figure 3.. CCB effect is ERK1/2- and AT1R-dependent in wild-type (WT) and Marfan mice.
(A) Western blot analysis of the aortic root and ascending aorta in 5-month-old mice. Number of mice per group = 4 (2 male, 2 female). (B) Mean (±2 SEM) ascending aortic growth from 2 to 4 months of age. Number of mice per group (male/female) = WT placebo 9 (5/4), WT amlodipine 8 (4/4), WT amlodipine + RDEA119 7 (3/4), Marfan placebo 9 (4/5), Marfan amlodipine 10 (6/4), Marfan amlodipine + RDEA119 11 (6/5). (C) Survival curve from 2 to 4 months of age. (D) Western blot analysis of the aortic root and ascending aorta in 4-month-old mice. Number of mice per group = 4 (2 male, 2 female). (E) Mean (±2 SEM) ascending aortic growth from 2 to 4 months of age. Number of mice per group (male/female) = WT placebo 11 (6/5), WT amlodipine 11 (6/5), WT amlodipine + losartan 8 (4/4), Marfan placebo 7 (4/3), Marfan amlodipine 6 (3/3), Marfan amlodipine + losartan 9 (4/5). (F) Western blot analysis of the aortic root and ascending aorta in 4-month-old mice. Number of mice per group = 3 (2 male, 1 female; or 1 male, 2 female). Plac, placebo; Aml, amlodipine; RDEA, RDEA119; Los, losartan; Geno, genotype; Treat, treatment; I/A, interaction. DOI:http://dx.doi.org/10.7554/eLife.08648.007
Figure 3—figure supplement 1.. CCB effect is…
Figure 3—figure supplement 1.. CCB effect is ERK1/2- and AT1R-dependent in wild-type (WT) and Marfan mice.
(S1) Representative latex images, VVG and trichrome staining in 4-month-old male mice. Latex scale bar: 2 mm. VVG and trichrome scale bar: 40 μm. (S2) Mean (±2 SEM) aortic architecture score in 4-month-old mice. Number of mice per group = 4 (2 male, 2 female). Plac, placebo; Aml, amlodipine; RDEA, RDEA119. DOI:http://dx.doi.org/10.7554/eLife.08648.008
Figure 4.. PKC activation in placebo- and…
Figure 4.. PKC activation in placebo- and CCB-treated wild-type (WT) and Marfan mice.
(A) Western blot analysis of the aortic root and proximal ascending aorta in 4-month-old mice. Number of mice per group = 4 (2 male, 2 female). (B) Western blot analysis of the aortic root and proximal ascending aorta in 4-month-old mice. Number of mice per group = 3 (2 male, 1 female; or 1 male, 2 female). (C) Mean (±2 SEM) ascending aortic growth from 2 to 4 months of age. Number of mice per group (male/female) = WT placebo 8 (4/4), WT amlodipine 9 (4/5), WT amlodipine + enzastaurin 8 (3/5), Marfan placebo 12 (7/5), Marfan amlodipine 8 (5/3), Marfan amlodipine + enzastaurin 8 (5/3). (D) Mean (±2 SEM) aortic root growth from 2 to 4 months of age. Number of mice per group (male/female) = WT placebo 8 (4/4), WT enzastaurin 6 (3/3), Marfan placebo 12 (7/5), Marfan enzastaurin 8 (4/4). (E) Western blot analysis of the aortic root and ascending aorta in 4-month-old mice. Number of mice per group = 4 (2 male, 2 female). Plac, placebo; NAb, neutralizing antibody; Los, losartan; Aml, amlodipine; Enz, enzastaurin; Geno, genotype; Treat, treatment; I/A, interaction. DOI:http://dx.doi.org/10.7554/eLife.08648.009
Figure 4—figure supplement 1.. PKC activation in…
Figure 4—figure supplement 1.. PKC activation in placebo- and CCB-treated wild-type (WT) and Marfan mice.
(S1) Representative latex-injected images of 4-month-old male mice. Scale bar: 2 mm. (S2) Representative VVG staining (upper panel) and Masson's trichrome staining (lower panel) of the proximal ascending aorta in 4-month-old male mice. Scale bar: 40 µm. (S3) Mean (±2 SEM) aortic architecture score of the aortic root and proximal ascending aorta in 4-month-old mice. Number of mice per group = 4 (2 male, 2 female). Scale: 1 (normal) to 5 (extensive damage). Plac, placebo; Aml, amlodipine; Enz, enzastaurin. DOI:http://dx.doi.org/10.7554/eLife.08648.010
Figure 5.. Effect of hydralazine in wild-type…
Figure 5.. Effect of hydralazine in wild-type (WT) and Marfan mice.
(A) Mean (±2 SEM) aortic root growth from 2 to 6 months of age. Number of mice per group (male/female) = WT placebo 9 (4/5), WT hydralazine 12 (7/5), Marfan placebo 15 (6/9), Marfan hydralazine 12 (6/6). Mean (±2 SEM) weight per group (in grams) at 6 months = 31.4 ± 2.4 g (WT placebo), 31.2 ± 3.1 g (WT hydralazine), 31.0 ± 2.7 g (Marfan placebo), 30.4 ± 3.5 g (Marfan hydralazine). (B) Western blot analysis of the aortic root in 6-month-old mice. Number of mice per group = 4 (2 male, 2 female). (C) Diagram illustrating key nodal points in Marfan mouse aortic disease pathogenesis. Drugs shown in red ameliorate aneurysm progression, while manipulations shown in blue exacerbate it. Plac, placebo; Hyd, hydralazine; Geno, genotype; Treat, treatment; I/A, interaction. DOI:http://dx.doi.org/10.7554/eLife.08648.011
Figure 5—figure supplement 1.. Effect of hydralazine…
Figure 5—figure supplement 1.. Effect of hydralazine in wild-type (WT) and Marfan mice.
(S1) Mean (±2 SEM) systolic and diastolic blood pressure, and heart rate, in 3-month-old mice. Number of mice per group = 8 (4 male; 4 female). (S2) Representative parasternal long-axis in vivo echocardiography images of 6-month-old male mice. Scale bar: 1 mm. (S3) Representative VVG staining (upper panel) and Masson's trichrome staining (lower panel) of the aortic root in 6-month-old mice. Scale bar: 40 µm. (S4) Mean (±2 SEM) aortic wall architecture score of the aortic root in 6-month-old mice. Number of mice per group = 4 (2 male, 2 female). Scale: 1 (normal) to 5 (extensive damage). (S5) Western blot analysis of the aortic root in 4-month-old mice. Number of mice per group = 4 (2 male, 2 female). Plac, placebo; Hyd, hydralazine; Aml, amlodipine; RDEA, RDEA119; Geno, genotype; Treat, treatment. DOI:http://dx.doi.org/10.7554/eLife.08648.012
Author response image 1.
Author response image 1.
DOI:http://dx.doi.org/10.7554/eLife.08648.016
Author response image 2.
Author response image 2.
DOI:http://dx.doi.org/10.7554/eLife.08648.017

References

    1. Chen X, Rateri DL, Howatt DA, Balakrishnan A, Moorleghen JJ, Morris AJ, Charnigo R, Cassis LA, Daugherty A. Amlodipine reduces AngII-induced aortic aneurysms and atherosclerosis in hypercholesterolemic mice. PLOS ONE. 2013;8:e81743. doi: 10.1371/journal.pone.0081743.
    1. Cohn RD, van Erp C, Habashi JP, Soleimani AA, Klein EC, Lisi MT, Gamradt M, ap Rhys CM, Holm TM, Loeys BL, Ramirez F, Judge DP, Ward CW, Dietz HC. Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nature Medicine. 2007;13:204–210. doi: 10.1038/nm1536.
    1. Cook JR, Clayton NP, Carta L, Galatioto J, Chiu E, Smaldone S, Nelson CA, Cheng SH, Wentworth BM, Ramirez F. Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;35:911–917. doi: 10.1161/ATVBAHA.114.305150.
    1. Deng C, Lu Q, Zhang Z, Rao T, Attwood J, Yung R, Richardson B. Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis Rheum. 2003;48:746–756. doi: 10.1002/art.10833.
    1. Doblinger E, Höcherl K, Mederle K, Kattler V, Walter S, Hansen PB, Jensen B, Castrop H. Angiotensin AT1 receptor-associated protein Arap1 in the kidney vasculature is suppressed by angiotensin II. American Journal of Physiology. Renal Physiology. 2012;302:F1313–F1324. doi: 10.1152/ajprenal.00620.2011.
    1. Gallo EM, Loch DC, Habashi JP, Calderon JF, Chen Y, Bedja D, van Erp C, Gerber EE, Parker SJ, Sauls K, Judge DP, Cooke SK, Lindsay ME, Rouf R, Myers L, ap Rhys CM, Kent KC, Norris RA, Huso DL, Dietz HC. Angiotensin II-dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis. The Journal of Clinical Investigation. 2014;124:448–460. doi: 10.1172/JCI69666.
    1. Gorelik G, Fang JY, Wu A, Sawalha AH, Richardson B. Impaired T cell protein kinase C delta activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus. The Journal of Immunology. 2007;179:5553–5563. doi: 10.4049/jimmunol.179.8.5553.
    1. Graff JR, McNulty AM, Hanna KR, Konicek BW, Lynch RL, Bailey SN, Banks C, Capen A, Goode R, Lewis JE, Sams L, Huss KL, Campbell RM, Iversen PW, Neubauer BL, Brown TJ, Musib L, Geeganage S, Thornton D. The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Research. 2005;65:7462–7469. doi: 10.1158/0008-5472.CAN-05-0071.
    1. Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F, Bedja D, Chen Y, Modiri AN, Judge DP, Dietz HC. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science. 2011;332:361–365. doi: 10.1126/science.1192152.
    1. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312:117–121. doi: 10.1126/science.1124287.
    1. Hartog AW, Franken R, Zwinderman AH, Groenink M, Mulder BJ. Current and future pharmacological treatment strategies with regard to aortic disease in Marfan syndrome. Expert Opinion on Pharmacotherapy. 2012;13:647–662. doi: 10.1517/14656566.2012.665446.
    1. Haskett D, Doyle JJ, Gard C, Chen H, Ball C, Estabrook MA, Encinas AC, Dietz HC, Utzinger U, Vande Geest JP, Azhar M. Altered tissue behavior of a non-aneurysmal descending thoracic aorta in the mouse model of Marfan syndrome. Cell and Tissue Research. 2012;347:267–277. doi: 10.1007/s00441-011-1270-y.
    1. Holm TM, Habashi JP, Doyle JJ, Bedja D, Chen Y, van Erp C, Lindsay ME, Kim D, Schoenhoff F, Cohn RD, Loeys BL, Thomas CJ, Patnaik S, Marugan JJ, Judge DP, Dietz HC. Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science. 2011;332:358–361. doi: 10.1126/science.1192149.
    1. Lee SJ, Kang JH, Choi SY, Suk KT, Kim DJ, Kwon OS. PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model. PLOS ONE. 2013;8:e55979. doi: 10.1371/journal.pone.0055979.
    1. Li Z, Jimenez SA. Protein kinase Cδ and c-Abl kinase are required for transforming growth factor β induction of endothelial-mesenchymal transition in vitro. Arthritis Rheum. 2011;63:2473–2483. doi: 10.1002/art.30317.
    1. Milewicz DM, Dietz HC, Miller DC. Treatment of aortic disease in patients with Marfan syndrome. Circulation. 2005;111:e150–e157. doi: 10.1161/01.CIR.0000155243.70456.F4.
    1. Moran D. Voltage-dependent -L-type Ca2+ channels participate in regulating neural crest migration and differentiation. The American Journal of Anatomy. 1991;192:14–22. doi: 10.1002/aja.1001920103.
    1. Mulsow JJ, Watson RW, Fitzpatrick JM, O'Connell PR. Transforming growth factor-beta promotes pro-fibrotic behavior by serosal fibroblasts via PKC and ERK1/2 mitogen activated protein kinase cell signaling. Annals of Surgery. 2005;242:880–887. doi: 10.1097/. Discussion 887–889.
    1. Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai LY, Dietz HC. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nature Genetics. 2003;33:407–411. doi: 10.1038/ng1116.
    1. Ng CM, Cheng A, Myers LA, Martinez-Murillo F, Jie C, Bedja D, Gabrielson KL, Hausladen JM, Mecham RP, Judge DP, Dietz HC. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. The Journal of Clinical Investigation. 2004;114:1586–1592. doi: 10.1172/JCI200422715.
    1. Olivares Reyes JA, Shah BH, Hernández-Aranda J, García-Caballero A, Farshori MP, García-Sáinz JA, Catt KJ. Agonist-induced interactions between angiotensin AT1 and epidermal growth factor receptors. Molecular Pharmaceutics. 2005;68:356–364.
    1. Olson ER, Shamhart PE, Naugle JE, Meszaros JG. Angiotensin II-induced extracellular signal-regulated kinase 1/2 activation is mediated by protein kinase Cdelta and intracellular calcium in adult rat cardiac fibroblasts. Hypertension. 2008;51:704–711. doi: 10.1161/HYPERTENSIONAHA.107.098459.
    1. Ramachandran KV, Hennessey JA, Barnett AS, Yin X, Stadt HA, Foster E, Shah RA, Yazawa M, Dolmetsch RE, Kirby ML, Pitt GS. Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development. The Journal of Clinical Investigation. 2013;123:1638–1646. doi: 10.1172/JCI66903.
    1. Rossi-Foulkes R, Roman MJ, Rosen SE, Kramer-Fox R, Ehlers KH, O'Loughlin JE, Davis JG, Devereux RB. Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome. The American Journal of Cardiology. 1999;83:1364–1368. doi: 10.1016/S0002-9149(99)00101-0.
    1. Ruvolo PP, Zhou L, Watt JC, Ruvolo VR, Burks JK, Jiffar T, Kornblau S, Konopleva M, Andreeff M. Targeting PKC-mediated signal transduction pathways using enzastaurin to promote apoptosis in acute myeloid leukemia-derived cell lines and blast cells. Journal of Cellular Biochemistry. 2011;112:1696–1707. doi: 10.1002/jcb.23090.
    1. Ryer EJ, Hom RP, Sakakibara K, Nakayama KI, Nakayama K, Faries PL, Liu B, Kent KC. PKCdelta is necessary for Smad3 expression and transforming growth factor beta-induced fibronectin synthesis in vascular smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:780–786. doi: 10.1161/.
    1. Salim MA, Alpert BS, Ward JC, Pyeritz RE. Effect of beta-adrenergic blockade on aortic root rate of dilation in the Marfan syndrome. The American Journal of Cardiology. 1994;74:629–633. doi: 10.1016/0002-9149(94)90762-5.
    1. Shah BH, Catt KJ. Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells: roles of protein kinase Cdelta, Src/proline-rich tyrosine kinase 2, and epidermal growth receptor trans-activation. Molecular Pharmaceutics. 2002;61:343–351. doi: 10.1124/mol.61.2.343.
    1. Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury. American Journal of Physiology. Heart and Circulatory Physiology. 2015;15:H894–H903. doi: 10.1152/ajpheart.00333.2014.
    1. Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan's syndrome. The New England Journal of Medicine. 1994;330:1335–1341. doi: 10.1056/NEJM199405123301902.
    1. Silverman DI, Burton KJ, Gray J, Kouchoukos NT, Roman MJ, Boxer M, Devereux RB, Tsipouras P. Life expectancy in the Marfan syndrome. The American Journal of Cardiology. 1995;15:157–160. doi: 10.1016/S0002-9149(00)80066-1.
    1. Takahashi K, Matsumoto Y, Do e Z, Kanazawa M, Satoh K, Shimizu T, Sato A, Fukumoto Y, Shimokawa H. Combination therapy with atorvastatin and amlodipine suppresses angiotensin II-induced aortic aneurysm formation. PLOS ONE. 2013;8:e72558. doi: 10.1371/journal.pone.0072558.
    1. Uchiyama-Tanaka Y, Matsubara H, Nozawa Y, Murasawa S, Mori Y, Kosaki A, Maruyama K, Masaki H, Shibasaki Y, Fujiyama S, Nose A, Iba O, Hasagawa T, Tateishi E, Higashiyama S, Iwasaka T. Angiotensin II signaling and HB-EGF shedding via metalloproteinase in glomerular mesangial cells. Kidney International. 2001;60:2153–2163. doi: 10.1046/j.1523-1755.2001.00067.x.
    1. von Kodolitsch Y, Robinson PN. Marfan syndrome: an update of genetics, medical and surgical management. Heart. 2007;93:755–760. doi: 10.1136/hrt.2006.098798.
    1. Williams A, Davies S, Stuart AG, Wilson DG, Fraser AG. Medical treatment of Marfan syndrome: a time for change. Heart. 2008;94:414–421. doi: 10.1136/hrt.2006.109454.
    1. Wu X, Zhu M, Fletcher JA, Giobbie-Hurder A, Hodi FS. The protein kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanoma. PLOS ONE. 2012;7:e29622. doi: 10.1371/journal.pone.0029622.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir