Abstract 15232: Role of Bmp Signals in Marfan Syndrome
Fibrillin-1 (Fbn-1) is known for Marfan syndrome (MFS), with which patients have complex symptoms found in the heart, blood vessels, bones and eyes. About 1 in 5,000 people have Marfan syndrome. Aortic aneurysm of Marfan syndrome patients is the most risk that results in sudden death. However, there are still Marfan syndrome patients without Fbn-1 mutation, or mutation of other genes associated with Marfan syndrome. In our study, we found that Bmp2/4/7 triple CKO (Mef2c-Cre; Bmp2/4/7f/f) exhibit disorganized smooth muscle cells in tuncus. Further characterization of these cells revealed that they are multi-potent cells expressing both sarcomeric myosin and α-smooth muscle actin. Interestingly, we found that Isl-1, the cardiac progenitor gene, was persistently expressed in Bmp2/4/7 mutant. Bioinformatic analysis and ChIP-seq suggest Smad binding to Fbn-1 chromatin. And both mRNA and protein level of Fbn-1 are decreased in the absence of Bmp2/4/7. Similar to Fbn-1 mutant, pSmad2 is dramatically activated in the truncus of Bmp2/4/7 tCKO. To further investigate the interaction between Fbn-1 and Bmp signal pathway, we crossed Fbnc1039g/+ to Mef2c-Cre;Bmp4f/+ mice. Heterozygous for both Bmp4 and Fbn-1 exhibit dilated aorta root examined by echocardiography, which indicates that loss of Bmp4 aggravates aorta aneurysm in Fbn mutant mice. Moreover, we introduced overexpression of miR-17-92 in Bmp4/7 dCKO (Mef2c-Cre;Bmp4/7f/f) and found rescue in truncus morphology and suppress of Tgf-β signal pathway. Our study will provide new insight into the Marfan syndrome diagnosis and probably treatment.
- © 2013 by American Heart Association, Inc.