Abstract 18640: Recombinant Bone Morphogenetic Protein 9 is a Novel Therapeutic That Rescues Cardiac Fibrosis and Improves Cardiac Function in Heart Failure
Cardiac fibrosis remains a significant target of therapy for patients with heart failure (HF). Bone morphogenetic protein 9 (BMP9) is a vascular quiescence factor that signals via the downstream effector, Smad1. No studies have explored a role for BMP9/Smad1 signaling in HF. We hypothesized that BMP9 limits cardiac fibrosis by promoting signaling via Smad1 in HF. We first determined that BMP9 protein levels are increased in the left ventricle (LV) of human subjects with HF compared to non-HF controls (n=8/group) and in male wild-type (WT) mice after 2 and 8 weeks of thoracic aortic constriction (TAC). Next, we tested BMP9-dependent regulation of TGFb1-induced Type I collagen synthesis in vitro using human cardiac fibroblasts (hCF). Compared to scrambled siRNA, silencing BMP9 increased collagen expression in hCF with or without TGFb1 stimulation. In contrast, rBMP9 treatment attenuated TGFb1 induced collagen synthesis by hCF in a dose-dependent manner. Compared to vehicle, recombinant BMP9 (rBMP9) increased pSmad1 and reduced pSmad3 levels after treatment with TGFb1. To explore a role for BMP9 in HF, we identified that, compared to WT, BMP9-/- mice exhibit a 4-fold increase in LV collagen expression after 2 weeks of TAC. We then tested whether treatment with rBMP9 rescues mice with established LV fibrosis. Male WT mice (n=40) were subject to 4 weeks of TAC. After 4 weeks of TAC, 20 mice survived to randomization to once daily rBMP9 or vehicle injections for an additional 4 weeks. Compared to Vehicle, rBMP9 treatment improved LV fractional shortening (p<0.01), reduced LV end-diastolic pressure (p<0.01), and increased LV dP/dTmax (p=0.03). Compared to Vehicle, rBMP9 treatment increased total body mass (p=0.02) and reduced both lung mass (p<0.01) and LV mass (p<0.01) after TAC. rBMP9 reduced LV fibrosis (p<0.01), Type I collagen mRNA and protein expression, and increased myocardial capillary density compared to vehicle treated mice. rBMP9, not vehicle, increased LV levels of phosphorylated Smad1 and reduced phosphorylated Smad-3 levels. We introduce a new role for BMP9 in HF and identified that rBMP9 may represent a novel therapeutic approach to rescue maladaptive cardiac remodeling by limiting fibrosis and promoting myocardial capillary density in HF.
Author Disclosures: K.J. Morine: None. X. Qiao: None. V. Paruchuri: None. Y. Zhang: None. M. Aronovitz: None. R. Karas: None. N.K. Kapur: None.
- © 2016 by American Heart Association, Inc.