Aldosteronism and peripheral blood mononuclear cell activation: a neuroendocrine-immune interface.
Aldosteronism eventuates in a proinflammatory/fibrogenic vascular phenotype of the heart and systemic organs. It remains uncertain whether peripheral blood mononuclear cells (PBMCs) are activated before tissue invasion by monocytes/macrophages and lymphocytes, as is the case for responsible pathogenic mechanisms. Uninephrectomized rats treated for 4 weeks with dietary 1% NaCl and aldosterone (ALDOST, 0.75 microg/h) with or without spironolactone (Spi, 100 mg/kg per daily gavage) were compared with unoperated/untreated and uninephrectomized/salt-treated controls. Before intramural coronary vascular lesions appeared at week 4 of ALDOST, we found (1) a reduction of PBMC cytosolic free [Mg2+]i, together with intracellular Mg2+ and Ca2+ loading, whereas plasma and cardiac tissue Mg2+ were no different from controls; (2) increased H2O2 production by monocytes and lymphocytes together with upregulated PBMC gene expression of oxidative stress-inducible tyrosine phosphatase and Mn2+-superoxide dismutase and the presence of 3-nitrotyrosine in CD4+ and ED-1-positive inflammatory cells that had invaded intramural coronary arteries; (3) B-cell activation, including transcription of immunoglobulins, intracellular adhesion molecule-1, and CC and CXC chemokines and their receptors; (4) expansion of B lymphocyte subset and myosin heavy chain class II-expressing lymphocytes; and (5) autoreactivity with gene expression for antibodies to acetylcholine receptors and a downregulation of RT-6.2, which is in keeping with cell activation and associated with autoimmunity. Spi cotreatment attenuated the rise in intracellular Ca2+, the appearance of oxidative/nitrosative stress in PBMCs and invading inflammatory cells, and alterations in PBMC transcriptome. Thus, aldosteronism is associated with an activation of circulating immune cells induced by iterations in PBMC divalent cations and transduced by oxidative/nitrosative stress. ALDO receptor antagonism modulates this neuroendocrine-immune interface. The full text of this article is available online at http://www.circresaha.org.
Department of Obstetrics & Gynecology, University of Tennessee Health Science Center, Memphis, Tenn, Memphis, Tenn 38163, USA.
Robert A
RA
Ahokas
Kenneth J
KJ
Warrington
Ivan C
IC
Gerling
Yao
Y
Sun
Linus A
LA
Wodi
Paula A
PA
Herring
Li
L
Lu
Syamal K
SK
Bhattacharya
Arnold E
AE
Postlethwaite
Karl T
KT
Weber
D000450:Aldosterone; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002469:Cell Separation; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005802:Genes, MHC Class II / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D006929:Hyperaldosteronism / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008274:Magnesium / Q000378:metabolism; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009206:Myocardium / Q000378:metabolism; D009392:Nephrectomy; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013148:Spironolactone / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; C002744:3-nitrotyrosine; D014443:Tyrosine; D000450:Aldosterone; D006861:Hydrogen Peroxide; D008274:Magnesium; D002118:Calcium