Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways

Arterioscler Thromb Vasc Biol. 2016 May;36(5):874-85. doi: 10.1161/ATVBAHA.115.307031. Epub 2016 Mar 10.

Abstract

Objective: Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms.

Approach and results: Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury. MMRKO reduced intima area and intima/media ratio, Ki67- and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67- and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67-positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-κB (NF-κB) pathway was also inhibited by MMRKO, manifested by decreased p-IκB kinase-β and p-IκBα, increased IκBα expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages.

Conclusions: Selective deletion of MR in myeloid cells limits macrophage accumulation and vascular inflammation and, therefore, inhibits neointimal hyperplasia and vascular remodeling. Mechanistically, MR deficiency suppresses migration and proliferation of macrophages and leads to less vascular smooth muscle cell activation. At the molecular level, MR deficiency suppresses macrophage inflammatory response via SGK1-AP1/NF-κB pathways.

Keywords: femoral artery; hyperplasia; macrophage; mineralocorticoid receptor; myeloid cells.

MeSH terms

  • Animals
  • Cell Movement
  • Cell Proliferation
  • Coculture Techniques
  • Disease Models, Animal
  • Femoral Artery / enzymology
  • Femoral Artery / injuries
  • Femoral Artery / metabolism
  • Genetic Predisposition to Disease
  • Hyperplasia
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Inflammation / enzymology*
  • Inflammation / genetics
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Macrophages / enzymology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / injuries
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • NF-kappa B / metabolism*
  • Neointima*
  • Paracrine Communication
  • Phenotype
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RAW 264.7 Cells
  • RNA Interference
  • Receptors, Mineralocorticoid / deficiency*
  • Receptors, Mineralocorticoid / genetics
  • Signal Transduction
  • Time Factors
  • Transcription Factor AP-1 / metabolism*
  • Transfection
  • Vascular Remodeling
  • Vascular System Injuries / enzymology*
  • Vascular System Injuries / genetics
  • Vascular System Injuries / pathology
  • Vascular System Injuries / prevention & control

Substances

  • Immediate-Early Proteins
  • NF-kappa B
  • Receptors, Mineralocorticoid
  • Transcription Factor AP-1
  • Protein Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase