Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Cardiac tissue injury and remodeling is dependent upon MR regulation of activation pathways in cardiac tissue macrophages (#11)

Jimmy Shen 1
  1. Monash Health and Hudson Institute of Medical Research, Clayton, VIC, Australia

Chronic mineralocorticoid receptor (MR) activation is a pathological state shared by diseases such as primary aldosteronism and heart failure, featuring cardiovascular tissue inflammation and remodelling.  We have previously demonstrated that macrophage MR signalling is an important mediator of cardiac tissue inflammation and fibrosis. The goal of the present study was to determine the cellular mechanisms of MR signalling in macrophages that promote cardiac tissue injury and remodelling. We sought to identify specific markers of MR signalling in isolated tissue macrophages (cardiac, aortic) vs splenic mononuclear cells from wild-type and myeloid MR-null mice given vehicle/salt or deoxycorticosterone (DOC)/salt for 8 weeks. Cardiac tissue fibrosis in response to 8 weeks of DOC/salt treatment was found in the hearts from wild-type but not myeloid MR-null mice. This was associated with an increased expression of the profibrotic markers TGF-β1 and matrix metalloproteinase-12 and type 1 inflammatory markers TNF and chemokine (C-X-C motif) ligand-9 in cardiac macrophages. Differential expression of immunomodulatory M2-likemarkers (eg, arginase-1,macrophage scavenger receptor 1) was dependent on the tissue location of wild-type and MR-null macrophages. Finally, intact MR signalling is required for the phosphorylation of c-Jun NH2-terminal kinase in response to a proinflammatory stimulus in bone marrow monocytes/macrophages in culture. These data suggest that the activation of the c-Jun NH2- terminal kinase pathway in macrophages after a tissue injury and inflammatory stimuli in the DOC/salt model is MR dependent and regulates the transcription of downstream profibrotic factors, which may represent potential therapeutic targets in heart failure patients.