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Myeloid Mineralocorticoid Receptor Transcriptionally Regulates P-Selectin Glycoprotein Ligand-1 and Promotes Monocyte Trafficking and Atherosclerosis.

AbstractObjective:
MR (mineralocorticoid receptor) activation associates with increased risk of cardiovascular ischemia while MR inhibition reduces cardiovascular-related mortality and plaque inflammation in mouse atherosclerosis. MR in myeloid cells (My-MR) promotes inflammatory cell infiltration into injured tissues and atherosclerotic plaque inflammation by unclear mechanisms. Here, we examined the role of My-MR in leukocyte trafficking and the impact of sex.
Approach and Results:
We confirm in vivo that My-MR deletion (My-MR-KO) in ApoE-KO mice decreased plaque size. Flow cytometry revealed fewer plaque macrophages with My-MR-KO. By intravital microscopy, My-MR-KO significantly attenuated monocyte slow-rolling and adhesion to mesenteric vessels and decreased peritoneal infiltration of myeloid cells in response to inflammatory stimuli in male but not female mice. My-MR-KO mice had significantly less PSGL1 (P-selectin glycoprotein ligand 1) mRNA in peritoneal macrophages and surface PSGL1 protein on circulating monocytes in males. In vitro, MR activation with aldosterone significantly increased PSGL1 mRNA only in monocytes from MR-intact males. Similarly, aldosterone induced, and MR antagonist spironolactone inhibited, PSGL1 expression in human U937 monocytes. Mechanistically, aldosterone stimulated MR binding to a predicted MR response element in intron-1 of the PSGL1 gene by ChIP-qPCR. Reporter assays demonstrated that this PSGL1 MR response element is necessary and sufficient for aldosterone-activated, MR-dependent transcriptional activity.
Conclusions:
These data identify PSGL1 as a My-MR target gene that drives leukocyte trafficking to enhance atherosclerotic plaque inflammation. These novel and sexually dimorphic findings provide insight into increased ischemia risk with MR activation, cardiovascular protection in women, and the role of MR in atherosclerosis and tissue inflammation.
AuthorsJoshua J Man, Qing Lu, M Elizabeth Moss, Brigett Carvajal, Wendy Baur, Amanda E Garza, Roy Freeman, Marina Anastasiou, Njabulo Ngwenyama, Gail K Adler, Pilar Alcaide, Iris Z Jaffe
JournalArteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 41 Issue 11 Pg. 2740-2755 (11 2021) ISSN: 1524-4636 [Electronic] United States
PMID34615372 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Video-Audio Media)
Chemical References
  • Membrane Glycoproteins
  • Mineralocorticoid Receptor Antagonists
  • NR3C2 protein, human
  • Nr3c2 protein, mouse
  • P-selectin ligand protein
  • Receptors, Mineralocorticoid
  • Spironolactone
Topics
  • Adult
  • Animals
  • Aorta, Thoracic (metabolism, pathology)
  • Aortic Diseases (genetics, metabolism, pathology, prevention & control)
  • Atherosclerosis (genetics, metabolism, pathology, prevention & control)
  • Cell Adhesion (drug effects)
  • Disease Models, Animal
  • Female
  • HEK293 Cells
  • Humans
  • Hypoglycemia (drug therapy, genetics, metabolism)
  • Leukocyte Rolling (drug effects)
  • Macrophages, Peritoneal (metabolism, pathology)
  • Male
  • Membrane Glycoproteins (genetics, metabolism)
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Middle Aged
  • Mineralocorticoid Receptor Antagonists (therapeutic use)
  • Monocytes (drug effects, metabolism, pathology)
  • Randomized Controlled Trials as Topic
  • Receptors, Mineralocorticoid (drug effects, genetics, metabolism)
  • Sex Factors
  • Signal Transduction
  • Spironolactone (therapeutic use)
  • Transcription, Genetic
  • Transendothelial and Transepithelial Migration
  • Treatment Outcome
  • U937 Cells
  • Young Adult

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