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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2020.1
- 수록면
- 98 - 103 (6page)
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초록· 키워드
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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.
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참고문헌 (18)
참고문헌 신청
Akhurst, R. J. / 2012 / Targeting the TGFβ signalling pathway in disease / Nat. Rev. Drug Discov 11:790~811
Dietz, H. C. / 1991 / Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene / Nature 352:337~339
Habashi, J. P. / 2006 / Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome / Science 312:117~121
Herbertz, S. / 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
Hibender, S. / 2016 / Resveratrol inhibits aortic root dilatation in the Fbn1C1039G/+ marfan mouse model / Arterioscler. Thromb. Vasc. Biol. 36:1618~1626
Dietz, H. C. / 1991 / Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene / Nature 352:337~339
Habashi, J. P. / 2006 / Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome / Science 312:117~121
Herbertz, S. / 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
Hibender, S. / 2016 / Resveratrol inhibits aortic root dilatation in the Fbn1C1039G/+ marfan mouse model / Arterioscler. Thromb. Vasc. Biol. 36:1618~1626
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