Targeting BMPR2 Signaling to Improve Right Ventricular Function in Congenital Heart Disease
Abstract
In our in vitro experiments we found that increasing BMPR2 signaling with FK506 prevented endothelial mesenchymal (EndMT) transition of cardiac endothelial cells in response to TGF-b. Furthermore, increasing BMPR2 signaling decreased collagen production and proliferation of human cardiac fibroblasts. Reduced BMPR2 signaling promoted EndMT and activation of cardiac fibroblasts in vitro, which was blocked by the repurposed drug FK506 (Tacrolimus). In vivo, increasing BMPR2 signaling with FK506 reduced the development of cardiac fibrosis and increased the systolic ejection fraction as well as cardiac strain as assessed by cardiac MRI in a mouse model of increased right ventricular (RV) afterload leading to progressive right heart failure. This model mimics the RV afterload in congenital heart disease in children. The distribution of the fibrosis characteristic of RV pressure overload was located in a perivascular area around coronary arteries as well as interstitially in the RV free wall. Lineage tracing experiments documented that the process of endothelial mesenchymal transition only minimally contributed to the observed cardiac fibrosis, but that the fibrosis was rather due to activation and proliferation of resident cardiac fibroblasts. Tacrolimus improved the RV function even in non-BMPR2 deficient animals, suggesting that it might be beneficial to improve RV function in situation of RV afterload, irrespectable of their BMPR2 status.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1152600
Entities
People
- Edda Spiekerkoetter
- Mario Boehm
- Ross Metzger
- Xuefei Tian
Organizations
- Stanford University