Abstract

Right Ventricular (RV) function is the predominant determinant of survival in patients suffering from pulmonary arterial hypertension (PAH). In pre-clinical models, pharmacological activation of bone morphogenetic protein (BMP) signaling with FK506 (Tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three end-stage PAH patients. Whether FK506 has direct effects on the pressure overloaded RV 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 wildtype and heterozygous Bmpr2 mutant mice. Right ventricular function and strain were assessed longitudinally via cardiac magnetic resonance (CMR) 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 (hCFs) and endothelial cells. In mice, low BMP signaling in the RV 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 hCFs as BMPR2 co-receptor to reduce TGFbeta1-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.

View details for DOI 10.1165/rcmb.2020-0528OC

View details for PubMedID 33938785