Aldosteronism and Peripheral Blood Mononuclear Cell Activation

Abstract

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 g/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 2ϩ ] i , together with intracellular Mg 2ϩ and Ca 2ϩ loading, whereas plasma and cardiac tissue Mg 2ϩ 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 2ϩ -superoxide dismutase and the presence of 3-nitrotyrosine in CD4ϩ 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 2ϩ , 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. (Circ Res. 2003;93:e124-e135.) Key Words: aldosterone Ⅲ peripheral blood mononuclear cells Ⅲ hydrogen peroxide production Ⅲ cytosolic free Mg 2ϩ and Ca 2ϩ Ⅲ transcriptome I rrespective of its etiologic origins, asymptomatic ventricular systolic dysfunction eventuates in an activation of the circulating renin-angiotensin-aldosterone system (RAAS), whose effector hormones contribute to the appearance of the congestive heart failure (CHF) syndrome. A chronic systemic illness ensues that features oxidative/nitrosative stress in such diverse tissues as skeletal muscle, peripheral blood mononuclear cells (PBMCs) (monocytes and lymphocytes), and heart 1-11 ; elevated circulating levels of proinflammatory cytokines and chemokines [12][13][14][15][16][17][18][19][20][21] ; and a wasting syndrome that eventuates in cachexia. 22 Pharmacological modulation of RAAS effector hormones has proven clinical benefits in patients with CHF. [23][24][25][26][27] A ro...

From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

“…We found increased Ca 2+ levels in the myocardium and PBMC during pre-clinical, clinical and pathological stages, accompanied by biomarker evidence of oxidative stress that included increased levels of malondialdehyde and 8-isoprostane in the heart and increased H 2 O 2 production by PBMC. 14,62,64,65 Metabolic studies accounted for the marked increase in urinary and fecal excretion of Ca 2+ and Mg 2+ during ALDOST, which leads to plasma-ionized hypocalcemia and hypomagnesemia. The calciumsensing receptor of the parathyroid glands, in turn, responds to hypocalcemia with increased secretion of PTH.…”

“…62 Also contributory to hypozincemia is a coordinated selective translocation of Zn 2+ to the sites of tissue injury, facilitated by corresponding upregulation of a Zn 2+ -binding protein, metallothionein (MT)-1 in targeted tissues. 62,86 We also used 65 Zn to systematically monitor Zn 2+ kinetics during 1 and 4 weeks of ALDOST. A simultaneous fall in plasma 65 Zn, and a selective accumulation of 65 Zn, was found at sites of injury that included its translocation to freshly incised skin at week 1 caused by osmotic minipump implantation, as well as the injured heart and kidneys at week 4.…”

“…62,86 We also used 65 Zn to systematically monitor Zn 2+ kinetics during 1 and 4 weeks of ALDOST. A simultaneous fall in plasma 65 Zn, and a selective accumulation of 65 Zn, was found at sites of injury that included its translocation to freshly incised skin at week 1 caused by osmotic minipump implantation, as well as the injured heart and kidneys at week 4. This intracellular trafficking of 65 Zn to injured tissues was facilitated by the upregulation of MT-1.…”

“…A simultaneous fall in plasma 65 Zn, and a selective accumulation of 65 Zn, was found at sites of injury that included its translocation to freshly incised skin at week 1 caused by osmotic minipump implantation, as well as the injured heart and kidneys at week 4. This intracellular trafficking of 65 Zn to injured tissues was facilitated by the upregulation of MT-1. 87 However, at week 4 there was a contemporaneous decline in 65 Zn in healed skin and bone, which serve as Zn 2+ reservoirs in an attempt to resolve hypozincemia.…”

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

“…11,12 Although the mechanisms underlying these aldosterone-induced changes are incompletely understood, some studies have suggested that these effects of aldosterone are independent of blood pressure or angiotensin levels 13 and may involve increased oxidative stress and inflammation. 12,14 However, because these data originate from experimental models of high-aldosterone hypertension involving unilateral nephrectomy, aldosterone infusion, and/or high-salt diet, 11,12,15,16 it is unclear whether aldosterone is involved in myocardial remodeling due to pressure overload and, if so, whether the effects of aldosterone are associated with oxidative stress and inflammation, as observed in the models of high aldosterone.…”