Aldosteronism: An immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype

Chronic inappropriate (relative to dietary Na⁺ intake) elevations in circulating aldosterone (ALDO), termed aldosteronism, are associated with remodeling of intramural arteries of the right and left heart. Lesions appear at week 4 of treatment with ALDO and 1% dietary NaCl in uninephrectomized rats (ALDOST) and include invading monocytes, macrophages and lymphocytes with intracellular evidence of oxidative and nitrosative stress, myofibroblasts, and perivascular fibrosis. In this study, we tested the hypothesis that an immunostimulatory state with activated circulating peripheral blood mononuclear cells (PBMCs) precedes this proinflammatory and profibrogenic cardiac phenotype and is initiated by reduction in the cytosolic free Mg²⁺ concentration ([Mg²⁺]_i). At 1 and 4 wk of ALDOST (preclinical and clinical stages, respectively), we monitored serum Mg²⁺, PBMC [Mg²⁺]_i and cytosolic free [Ca²⁺] (via fluorimetry), and expressed genes (via microchip array) as well as markers of oxidative and nitrosative stress in plasma [α₁-antiproteinase activity (α₁-AP)] and cardiac tissue (immunohistochemical detection of gp91^phox subunit of NADPH oxidase and 3-nitrotyrosine). Age- and gender-matched unoperated and untreated (UO) rats and uninephrectomized salt-treated (UN) rats served as controls. Serum [Mg²⁺] was unchanged by ALDOST. In contrast with UO and UN, [Mg²⁺]_i and plasma α₁-AP were each reduced (P < 0.05) at weeks 1 and 4. The decline in PBMC [Mg²⁺]_i was accompanied by Ca²⁺ loading. Differential (twofold and higher) expression (up- and downregulation) in PBMC transcriptomes was present at week 1 and progressed at week 4. Involved were genes for the α₁-isoform of Na⁺-K⁺-ATPase, the ATP-dependent Ca²⁺ pump, antioxidant reserves, inducible nitric oxide synthase, and PBMC activation with autoimmune responses. Expression of 3-nitrotyrosine and activation of gp91^phox were seen in inflammatory cells that invaded intramural arteries. Thus early in aldosteronism (preclinical stage), an immunostimulatory state featuring activated circulating PBMCs with reduced ionized [Mg²⁺]_i and oxidative and nitrosative stress precedes and may even predispose to coronary vascular lesions that first appear at week 4.