Improving Right Ventricular Function by Increasing BMP Signaling with FK506.

Abstract

Right ventricular (RV) function is the predominant determinant of survival in patients with pulmonary arterial hypertension (PAH). In preclinical models, pharmacological activation of BMP (bone morphogenetic protein) signaling with FK506 (tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three patients with end-stage PAH. Whether FK506 has direct effects on the pressure-overloaded right ventricle is yet unknown. We hypothesized that increasing cardiac BMP signaling with FK506 improves RV structure and function in a model of fixed RV afterload after pulmonary artery banding (PAB). Direct cardiac effects of FK506 on the microvasculature and RV fibrosis were studied after surgical PAB in wild-type and heterozygous Bmpr2 mutant mice. RV function and strain were assessed longitudinally via cardiac magnetic resonance imaging during continuous FK506 infusion. Genetic lineage tracing of endothelial cells (ECs) was performed to assess the contribution of ECs to fibrosis. Molecular mechanistic studies were performed in human cardiac fibroblasts and ECs. In mice, low BMP signaling in the right ventricle exaggerated PAB-induced RV fibrosis. FK506 therapy restored cardiac BMP signaling, reduced RV fibrosis in a BMP-dependent manner independent from its immunosuppressive effect, preserved RV capillarization, and improved RV function and strain over the time course of disease. Endothelial mesenchymal transition was a rare event and did not significantly contribute to cardiac fibrosis after PAB. Mechanistically, FK506 required ALK1 in human cardiac fibroblasts as a BMPR2 co-receptor to reduce TGFβ1-induced proliferation and collagen production. Our study demonstrates that increasing cardiac BMP signaling with FK506 improves RV structure and function independent from its previously described beneficial effects on pulmonary vascular remodeling.

• Authors: Mario Boehm, Xuefei Tian, Md Khadem Ali, Yuqiang Mao, Kenzo Ichimura, Mingming Zhao, Kazuya Kuramoto, Svenja Dannewitz Prosseda, Giovanni Fajardo, Melanie J Dufva, Xulei Qin, Vitaly O Kheyfets, Daniel Bernstein, Sushma Reddy, Ross J Metzger, Roham T Zamanian, Francois Haddad, Edda Spiekerkoetter
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 65 Issue 3 Pg. 272-287 (09 2021) ISSN: 1535-4989 [Electronic] United States
• PMID: 33938785 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Bone Morphogenetic Proteins
• Bmpr2 protein, mouse
• Bone Morphogenetic Protein Receptors, Type II
• Tacrolimus

Topics

• Animals
• Bone Morphogenetic Protein Receptors, Type II (genetics, metabolism)
• Bone Morphogenetic Proteins (genetics, metabolism)
• Fibroblasts (metabolism)
• Fibrosis
• Humans
• Male
• Mice
• Mice, Mutant Strains
• Myocardium (metabolism)
• Pulmonary Arterial Hypertension (drug therapy, genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• Tacrolimus (pharmacology)
• Ventricular Function, Right (drug effects, genetics)