Aldosteronism and a proinflammatory vascular phenotype: role of Mg2+, Ca2+, and H2O2 in peripheral blood mononuclear cells.
BACKGROUND
Chronic, inappropriate (relative to dietary Na+) elevations in circulating aldosterone, such as occur in congestive heart failure, are accompanied by a proinflammatory vascular phenotype involving the coronary and systemic vasculature. An immunostimulatory state with activated peripheral blood mononuclear cells (PBMCs) precedes this phenotype and is induced by a fall in cytosolic free [Mg2+]i and subsequent Ca2+ loading of these cells and transduced by oxidative/nitrosative stress.


RESULTS
We sought to further validate this hypothesis in rats with aldosterone/1%NaCl treatment (ALDOST) by using several interventions as cotreatment: a Mg2+-supplemented diet; amlodipine, a CCB; and N-acetylcysteine, an antioxidant. Blood samples were obtained at weeks 1 to 4 of ALDOST to monitor [Mg2+]i, [Ca2+]I, and H2O2 production in PBMCs. Coronal ventricular sections were examined for invading inflammatory cells and 3-nitrotyrosine labeling, a marker of oxidative/nitrosative stress. In response to ALDOST and compared with untreated controls, we found an early and persistent reduction in [Mg2+]i with a subsequent rise in [Ca2+]i and H2O2 production, each of which was either attenuated or abrogated by the Mg2+-supplemented diet and by N-acetylcysteine, whereas amlodipine prevented Ca2+ loading and an altered redox state. Cotreatment with these interventions either markedly attenuated or prevented the appearance of the proinflammatory coronary vascular phenotype and the presence of 3-nitrotyrosine in invading inflammatory cells.


CONCLUSIONS
We suggest that the immunostimulatory state that appears during aldosteronism and leads to a proinflammatory coronary vascular phenotype is induced by a fall in [Mg2+]i with Ca2+ loading of PBMCs and is transduced by H2O2 production in these cells.
Ahokas
Robert A
RA
Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, Tenn 38163, USA.
Sun
Yao
Y
Bhattacharya
Syamal K
SK
Gerling
Ivan C
IC
Weber
Karl T
KT
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000097:blood / Q000502:physiology*; D019587:Dietary Supplements; D006861:Hydrogen Peroxide / Q000097:blood*; D006929:Hyperaldosteronism / Q000150:complications* / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008274:Magnesium / Q000008:administration & dosage / Q000097:blood / Q000502:physiology* / Q000627:therapeutic use; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis; D014657:Vasculitis / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control
D015415:Biomarkers; D017673:Sodium Chloride, Dietary; D017311:Amlodipine; C002744:3-nitrotyrosine; D014443:Tyrosine; D006861:Hydrogen Peroxide; D008274:Magnesium; D002118:Calcium; D000111:Acetylcysteine