Cardiac Specific Gene Delivery of a Dual GC-A and GC-B Agonist, CD-NP, Mediates Anti-Hypertrophic Actions in a Model of Hypertensive Heart Disease beyond GC-A Activation Alone Via BNP

Abstract

Introduction: Hypertensive heart disease (HHD) is characterized by altered myocardial structure and function, which is leading cause of heart failure and death. CD-NP is a newly developed dual guanylyl cyclase (GC)-A and GC-B agonist that is currently in clinical trials in post acute heart failure as a chronically delivered peptide. CD-NP has direct anti-hypertrophic and anti-fibrotic actions independent of blood pressure lowering. Hypothesis: We hypothesized that cardiac overexpression of CD-NP would result in a superior anti-remodeling effect than a single GC-A agonist, BNP.Methods: Here we defined the chronic effects of cardiac overexpression of CDNP we using adeno-associated vector serotype 9 (AAV9) in spontaneously hypertensive rats (SHR). We further compared the cardiac action of CD-NP to those of the single GC-A agonist, BNP. Results: The main findings of the study are illustrated on figure 1. A single intravenous injection of AAV9 induced sustained overexpression of CD-NP and BNP in the heart of SHR as verified by ELISA. The CNP ELISA assay also detected modest, but significantly elevated levels of circulating CD-NP in plasma. More importantly, compared to chronic overexpression of BNP, that has previously shown to induce significant reduction of cardiac weight, CD-NP had greater anti-hypertrophic actions 5 weeks post injection (p!0.05). Importantly, the anti-hypertrophic effects of CD-NP occurred with no changes in BP, suggesting a direct cardiac effect of this autacoid. Conclusion: Our studies demonstrate successful sustained cardiac CD-NP overexpression through a single systemic gene delivery approach. Of note, this novel peptide that combines the anti-hypertrophic and anti-fibrotic actions of both GC-A and GC-B activation, resulted in a significant reduction of cardiac mass, which was independent of BP lowering action and greater than that of the single CG-A agonist, BNP. These studies underscore that gene delivery of CD-NP can be useful in the treatment of HHD.