Abstract 11323: In vitro and in vivo Actions of Ang1-7/BNP: A Novel Chimeric Peptide With Dual Actions Through the Natriuretic Peptide and Mas Receptors
Objectives: Cardiorenal protective actions of B-type natriuretic peptide (BNP) are mediated through guanylyl cyclase A (GC-A) and its second messenger cGMP, while protective actions of Angiotensin 1-7 (Ang1-7) are mediated by the Mas receptor (MasR) and its second messenger cAMP. We designed a novel chimeric fusion peptide of integrating key amino acids of human BNP and Ang1-7, to create ANG1-7/BNP. Our goal was to engineer a peptide with dual activation of GC-A and MasR, with the potential to limit cardiorenal disease by natriuretic, antiproliferative and RAAS suppressing actions.
Hypothesis: We hypothesized that ANG1-7/BNP would stimulate the GC-A and MasR in vitro, and that it would be biologically active in vivo.
Methods: HEK cells expressing either GC-A or MasR were stimulated with ANG1-7/BNP. Three groups of normal dogs received 45 minutes infusions of equimolar doses of Ang1-7 (n=5), BNP (n=5) or ANG1-7/BNP (n=6), and hemodynamic, renal and neurohumoral functions were assessed during infusion and two hours thereafter.
Results: In vitro GC-A or MasR stimulation by ANG1-7/BNP resulted in cGMP production at 10-10M, 10-8 M and 10-6 M, and cAMP release at 10-6 M and 10-5 M, respectively (p<0.05). In vivo, only ANG1-7/BNP reduced SVR while both BNP and ANG1-7/BNP lowered MAP and PCWP with the most sustained effect by ANG1-7/BNP. ANG1-7/BNP resulted in increasing CO and RBF, greater than the two other groups (p<0.05). HR increased in the ANG1-7/BNP group in association with the greatest decline in SVR and PCWP, and increase in RBF. ANG1-7/BNP had a stronger natriuretic effect compared to BNP (p<0.05). Urine excretion and renal generation of cGMP was higher in the ANG1-7/BNP group compared to BNP (p<0.05). Plasma cAMP was suppressed by BNP and ANG1-7/BNP, but renal generation of cAMP increased in the ANG1-7/BNP group.
Conclusion: The new chimeric fusion peptide ANG1-7/BNP is a first in class dual activator of GC-A/MasR in vitro. ANG1-7/BNP is biologically active when infused in a large animal, with systemic and renal cGMP activation, and potent hemodynamic and natriuretic properties. Through the separate signaling pathways of Ang1-7 and BNP, ANG1-7/BNP may represent a new and innovative therapy with the potential of preventing progression of cardiorenal disease.
- © 2013 by American Heart Association, Inc.