Affiliation:
1. From the Departments of Obstetrics & Gynecology (R.A.A.) and Surgery (S.K.B.) and Divisions of Cardiovascular Diseases (Y.S., L.A.W., L.L., K.T.W.), Connective Tissue Diseases (K.J.W., P.A.H., A.E.P.), and Endocrinology (I.C.G.), Department of Medicine, University of Tennessee Health Science Center, Memphis, Tenn.
Abstract
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 μg/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 [Mg
2+
]
i
, together with intracellular Mg
2+
and Ca
2+
loading, whereas plasma and cardiac tissue Mg
2+
were no different from controls; (2) increased H
2
O
2
production by monocytes and lymphocytes together with upregulated PBMC gene expression of oxidative stress–inducible tyrosine phosphatase and Mn
2+
-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 Ca
2+
, 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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
113 articles.
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