Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Transforming Growth Factor β Receptor Type I Inhibitor, Galunisertib, Has No Beneficial Effects on Aneurysmal Pathological Changes in Marfan Mice

  • Park, Jeong-Ho (College of Pharmacy, Chung-Ang University) ;
  • Kim, Min-Seob (College of Pharmacy, Chung-Ang University) ;
  • Ham, Seokran (College of Pharmacy, Chung-Ang University) ;
  • Park, Eon Sub (Department of Pathology, College of Medicine, Chung-Ang University) ;
  • Kim, Koung Li (College of Pharmacy, Chung-Ang University) ;
  • Suh, Wonhee (College of Pharmacy, Chung-Ang University)
  • Received : 2019.03.07
  • Accepted : 2019.06.04
  • Published : 2019.12.30
Download PDF
⟨ Previous Next ⟩

Abstract

Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 (Fbn1) gene, has vascular manifestations including aortic aneurysm, dissection, and rupture. Its vascular pathogenesis is assumed to be attributed to increased transforming growth factor β (TGFβ) signaling and blockade of excessive TGFβ signaling has been thought to prevent dissection and aneurysm formation. Here, we investigated whether galunisertib, a potent small-molecule inhibitor of TGFβ receptor I (TβRI), attenuates aneurysmal disease in a murine model of MFS (Fbn1C1039G/+) and compared the impact of galuninsertib on the MFS-related vascular pathogenesis with that of losartan, a prophylactic agent routinely used for patients with MFS. Fbn1C1039G/+ mice were administered galunisertib or losartan for 8 weeks, and their ascending aortas were assessed for histopathological changes and phosphorylation of Smad2 and extracellular signal-regulated kinase 1/2 (Erk1/2). Mice treated with galunisertib or losartan barely exhibited phosphorylated Smad2, suggesting that both drugs effectively blocked overactivated canonical TGFβ signaling in Fbn1C1039G/+ mice. However, galunisertib treatment did not attenuate disrupted medial wall architecture and only partially decreased Erk1/2 phosphorylation, whereas losartan significantly inhibited MFS-associated aortopathy and markedly decreased Erk1/2 phosphorylation in Fbn1C1039G/+ mice. These data unexpectedly revealed that galunisertib, a TβRI inhibitor, showed no benefits in aneurysmal disease in MFS mice although it completely blocked Smad2 phosphorylation. The significant losartan-induced inhibition of both aortic vascular pathogenesis and Smad2 phosphorylation implied that canonical TGFβ signaling might not prominently drive aneurysmal diseases in MFS mice.

Keywords

References

  1. Akhurst, R. J. and Hata, A. (2012) Targeting the TGF${\beta}$ signalling pathway in disease. Nat. Rev. Drug Discov. 11, 790-811. https://doi.org/10.1038/nrd3810
  2. Dietz, H. C., Cutting, C. R., Pyeritz, R. E., Maslen, C. L., Sakai, L. Y., Corson, G. M., Puffenberger, E. G., Hamosh, A., Nanthakumar, E. J., Curristin, S. M., Stetten, G., Meyers, D. A. and Francomano, C. A. (1991) Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337-339. https://doi.org/10.1038/352337a0
  3. Habashi, J. P., Judge, D. P., Holm, T. M., Cohn, R. D., Loeys, B. L., Cooper, T. K., Myers, L., Klein, E. C., Liu, G., Calvi, C., Podowski, M., Neptune, E. R., Halushka, M. K., Bedja, D., Gabrielson, K., Rifkin, D. B., Carta, L., Ramirez, F., Huso, D. L. and Dietz, H. C. (2006) Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312, 117-121. https://doi.org/10.1126/science.1124287
  4. Herbertz, S., Sawyer, J. S., Stauber, A. J., Gueorguieva, I., Driscoll, K. E., Estrem, S. T., Cleverly, A. L., Desaiah, D., Guba, S. C., Benhadji, K. A., Slapak, C. A. and Lahn, M. M. (2015) Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des. Devel. Ther. 9, 4479-4499.
  5. Hibender, S., Franken, R., van Roomen, C., Ter Braake, A., van der Made, I., Schermer, E. E., Gunst, Q., van den Hoff, M. J., Lutgens, E., Pinto, Y. M., Groenink, M., Zwinderman, A. H., Mulder, B. J., de Vries, C. J. and de Waard, V. (2016) Resveratrol inhibits aortic root dilatation in the Fbn1C1039G/+ marfan mouse model. Arterioscler. Thromb. Vasc. Biol. 36, 1618-1626. https://doi.org/10.1161/ATVBAHA.116.307841
  6. Holm, T. M., Habashi, J. P., Doyle, J. J., Bedja, D., Chen, Y., van Erp, C., Lindsay, M. E., Kim, D., Schoenhoff, F., Cohn, R. D., Loeys, B. L., Thomas, C. J., Patnaik, S., Marugan, J. J., Judge, D. P. and Dietz, H. C. (2011) Noncanonical TGF${\beta}$ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 332, 358-361. https://doi.org/10.1126/science.1192149
  7. Judge, D. P. and Dietz, H. C. (2005) Marfan’s syndrome. Lancet 366, 1965-1976. https://doi.org/10.1016/S0140-6736(05)67789-6
  8. Kim, K. L., Choi, C. and Suh, W. (2014) Analysis of disease progression-associated gene expression profile in fibrillin-1 mutant mice: new insight into molecular pathogenesis of marfan syndrome. Biomol. Ther. (Seoul) 22, 143-148. https://doi.org/10.4062/biomolther.2014.010
  9. Kim, K. L., Yang, J. H., Song, S. H., Kim, J. Y., Jang, S. Y., Kim, J. M., Kim, J. A., Sung, K. I., Kim, Y. W., Suh, Y. L., Suh, W. and Kim, D. K. (2013) Positive correlation between the dysregulation of transforming growth factor-beta1 and aneurysmal pathological changes in patients with Marfan syndrome. Circ. J. 77, 952-958. https://doi.org/10.1253/circj.CJ-12-0874
  10. Lavoie, P., Robitaille, G., Agharazii, M., Ledbetter, S., Lebel, M. and Lariviere, R. (2005) Neutralization of transforming growth factorbeta attenuates hypertension and prevents renal injury in uremic rats. J. Hypertens. 23, 1895-1903. https://doi.org/10.1097/01.hjh.0000182521.44440.c5
  11. Matt, P., Schoenhoff, F., Habashi, J., Holm, T., Van Erp, C., Loch, D., Carlson, O. D., Griswold, B. F., Fu, Q., De Backer, J., Loeys, B., Huso, D. L., McDonnell, N. B., Van Eyk, J. E. and Dietz, H. C. (2009) Circulating transforming growth factor-beta in Marfan syndrome. Circulation 120, 526-532. https://doi.org/10.1161/CIRCULATIONAHA.108.841981
  12. Neptune, E. R., Frischmeyer, P. A., Arking, D. E., Myers, L., Bunton, T. E., Gayraud, B., Ramirez, F., Sakai, L. Y. and Dietz, H. C. (2003) Dysregulation of TGF${\beta}$ activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407-411. https://doi.org/10.1038/ng1116
  13. Schleifenbaum, J., Kassmann, M., Szijarto, I. A., Hercule, H. C., Tano, J. Y., Weinert, S., Heidenreich, M., Pathan, A. R., Anistan, Y. M., Alenina, N., Rusch, N. J., Bader, M., Jentsch, T. J. and Gollasch, M. (2014) Stretch-activation of angiotensin II type 1a receptors contributes to the myogenic response of mouse mesenteric and renal arteries. Circ. Res. 115, 263-272. https://doi.org/10.1161/CIRCRESAHA.115.302882
  14. Serova, M., Tijeras-Raballand, A., Dos Santos, C., Albuquerque, M., Paradis, V., Neuzillet, C., Benhadji, K. A., Raymond, E., Faivre, S. and de Gramont, A. (2015) Effects of $TGF{\beta}$ signalling inhibition with galunisertib (LY2157299) in hepatocellular carcinoma models and in ex vivo whole tumor tissue samples from patients. Oncotarget 6, 21614-21627. https://doi.org/10.18632/oncotarget.4308
  15. Wisler, J. W., Harris, E. M., Raisch, M., Mao, L., Kim, J., Rockman, H. A. and Lefkowitz, R. J. (2015) The role of beta-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome. Am. J. Physiol. Heart Circ. Physiol. 309, H1516-H1527. https://doi.org/10.1152/ajpheart.00291.2015
  16. Xiong, W., Meisinger, T., Knispel, R., Worth, J. M. and Baxter, B. T. (2012) MMP-2 regulates Erk1/2 phosphorylation and aortic dilatation in Marfan syndrome. Circ. Res. 110, e92-e101. https://doi.org/10.1161/CIRCRESAHA.112.268268
  17. Yang, H. H., Kim, J. M., Chum, E., van Breemen, C. and Chung, A. W. (2009) Long-term effects of losartan on structure and function of the thoracic aorta in a mouse model of Marfan syndrome. Br. J. Pharmacol. 158, 1503-1512. https://doi.org/10.1111/j.1476-5381.2009.00443.x
  18. Zou, Y., Akazawa, H., Qin, Y., Sano, M., Takano, H., Minamino, T., Makita, N., Iwanaga, K., Zhu, W., Kudoh, S., Toko, H., Tamura, K., Kihara, M., Nagai, T., Fukamizu, A., Umemura, S., Iiri, T., Fujita, T. and Komuro, I. (2004) Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. Nat. Cell Biol. 6, 499-506. https://doi.org/10.1038/ncb1137

Cited by

  1. Blood pressure‐independent inhibition of Marfan aortic root widening by the angiotensin II receptor blocker valsartan vol.9, pp.10, 2021, https://doi.org/10.14814/phy2.14877
  2. CRISPR/Cas9 in zebrafish: An attractive model for FBN1 genetic defects in humans vol.9, pp.10, 2020, https://doi.org/10.1002/mgg3.1775