Abstract 18998: Macrophage-Specific Mineralocorticoid Receptor Antagonists for Cardiovascular Disease

Abstract

Background: Mineralocorticoid receptor antagonists (MRA) have consistently led to improved clinical outcomes in patients with cardiovascular disease. Despite these benefits, off-target effects have limited the use of MRAs. Studies have begun to define the molecular mechanisms underlying cell-specific MR signaling, with several groups demonstrating a pathologic role for macrophage-MR activation in animal models of heart failure. Objective: We sought to engineer and evaluate a macrophage-specific MRA (Mf-MRA) composed of three elements: a nanoparticle delivery platform, the MRA eplerenone, and a fluorogenic biomarker for therapeutic monitoring. Methods and Results: The individual elements of the Mf-MRA were assembled using click chemistry. Bone marrow-derived macrophages (BMDM) and control cell models were used to evaluate the cell-specificity and therapeutic efficacy of the Mf-MRA. Using flow cytometry, we found that the Mf-MRA internalizes and is activated specifically in macrophages and not other cells. To confirm the functionality of the Mf-MRA, we evaluated oxidative stress induction and inflammatory gene expression in BMDM in response to aldosterone (Aldo). Equivalent concentrations (1 μM) of spironolactone and the Mf-MRA blocked Aldo induced superoxide production (Figure 1). Additionally, the Mf-MRA blocked Aldo induction of TNFα gene transcription (p<0.005). Finally, preliminary studies in a murine heart failure model confirmed the macrophage-specific delivery and activation of the Mf-MRA. Conclusions: We have developed a novel, macrophage-specific MRA using a synthetic nanoparticle, a fluorogenic biomarker, and an established MRA. This cell-specific MRA combines targeted-delivery with therapeutic monitoring. We believe that this innovative platform will have unique diagnostic and therapeutic applications for a broad spectrum of cardiovascular diseases.