Transforming Growth Factor β Receptor Type I Inhibitor, Galunisertib, Has No Beneficial Effects on Aneurysmal Pathological Changes in Marfan Mice
Jeong-Ho Park1,†, Min-Seob Kim1,†, Seokran Ham1, Eon Sub Park2, Koung Li Kim1 and Wonhee Suh1,*
1College of Pharmacy, Chung-Ang University, Seoul 06974, 2Department of Pathology, College of Medicine, Chung-Ang University, Seoul 06974, Republic of Korea
*E-mail: wsuh@cau.ac.kr Tel: +82-2-820-5960, Fax: +82-2-816-7338

The first two authors contributed equally to this work.
Received: March 7, 2019; Revised: April 19, 2019; Accepted: June 4, 2019; Published online: July 9, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

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 losartaninduced inhibition of both aortic vascular pathogenesis and Smad2 phosphorylation implied that canonical TGFβ signaling might not prominently drive aneurysmal diseases in MFS mice.
Keywords: Galunisertib, Marfan syndrome, Thoracic aortic aneurysm, Transforming growth factor-β receptor I inhibitor


This Article


Cited By Articles
  • CrossRef (0)

e-submission

Archives