| First Author | Park JH | Year | 2019 |
| Journal | Biomol Ther (Seoul) | Pages | 98-103 |
| PubMed ID | 31284709 | Mgi Jnum | J:299045 |
| Mgi Id | MGI:6490096 | Doi | 10.4062/biomolther.2019.042 |
| Citation | Park JH, et al. (2019) Transforming Growth Factor beta Receptor Type I Inhibitor, Galunisertib, Has No Beneficial Effects on Aneurysmal Pathological Changes in Marfan Mice. Biomol Ther (Seoul) :98-103 |
| abstractText | 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 beta (TGFbeta) signaling and blockade of excessive TGFbeta signaling has been thought to prevent dissection and aneurysm formation. Here, we investigated whether galunisertib, a potent small-molecule inhibitor of TGFbeta receptor I (TbetaRI), attenuates aneurysmal disease in a murine model of MFS (Fbn1(C1039G/+)) 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. Fbn1(C1039G/+) 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 TGFbeta signaling in Fbn1(C1039G/+) 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 Fbn1(C1039G/+) mice. These data unexpectedly revealed that galunisertib, a TbetaRI 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 TGFbeta signaling might not prominently drive aneurysmal diseases in MFS mice. |
