Abstract 19444: Liver X Receptor Activation with AZ876 Exerts Cardiac-Specific Effects in Protection Against Pathological Cardiac Remodeling
Introduction: Liver X receptors (LXR) are ligand-activated transcription factors that function as master regulators of reverse cholesterol transport and inflammation. Recently, LXR activation has been shown to confer protection against cardiac hypertrophy and dysfunction. However, cell-specific expression and function of LXR in the heart is unknown. Using a novel high-affinity LXR agonist, AZ876, we aimed to investigate the antihypertrophic and antifibrotic potential of LXR activation in vivo and in vitro.
Methods: Pathological cardiac hypertrophy was induced in C57Bl6/J mice via transverse aortic constriction (TAC) for 6 weeks. During this period, AZ876 (AZ, 20 μmol/kg/day) and vehicle (veh) were administered in chow (N=7-10/group). In vitro studies were performed in isolated neonatal rat cardiomyocytes and adult rat cardiac fibroblasts. Leucine and proline incorporation assays were used to measure protein and collagen synthesis, respectively.
Results: AZ876 activation of LXR significantly reduced TAC-induced increases in heart weight, myocardial fibrosis, and cardiac dysfunction in murine hearts. At the molecular level, AZ876 suppressed upregulation of well-characterized hypertrophic and fibrosis genes, and further inhibited pro-hypertrophic and pro-fibrotic Tgfβ - phosphorylated SMAD2/SMAD3 signaling. In isolated cardiomyocytes and cardiac fibroblasts, RT-PCR and immunofluoresence microscopy confirmed nuclear expression of LXR in both these cell types. In cardiomyocytes, phenylephrine-stimulated protein synthesis was significantly decreased in response to AZ876 treatment, as well as reduced expression of hypertrophic genes, ANP, BNP, Acta1 and Rcan1, was observed. In cardiac fibroblasts, AZ876 prevented Tgfβ- and angiotensin II-induced fibroblast collagen synthesis and proliferation, and strongly inhibited the upregulation of the myofibroblastic marker, αSMA, and periostin mRNA levels.
Conclusion: Our results indicate that cardiomyocytes and cardiac fibroblasts are direct targets of LXR agonism, and the novel LXR agonist AZ876 exerts cytoprotective effects in vitro as well as in hypertrophic murine hearts. LXR may thus represent a putative molecular target for antihypertrophic and antifibrotic therapies.
Author Disclosures: M.V. Cannon: None. H. Yu: None. W.M. Candido: None. M.M. Dokter: None. E. Lindstedt: Employment; Significant; Employee of AstraZeneca. Other; Modest; Donation of AZ876 compound. H.H. Sillje: None. W.H. van Gilst: None. R.A. de Boer: None.
- © 2014 by American Heart Association, Inc.