Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of early angiotensin II/NG-nitro-L-arginine methyl ester-induced myocardial injury.

Division of Endocrinology, Hypertension and Diabetes, Department of Medicine, Brigham and Women's Hospital, 221 Longwood Ave, Boston, Mass 02115, USA.
Circulation (Impact Factor: 15.2). 12/2003; 108(20):2517-23. DOI: 10.1161/01.CIR.0000097000.51723.6F
Source: PubMed

ABSTRACT Angiotensin II (Ang II) increases levels of aldosterone and plasminogen activator inhibitor-1 (PAI-1). Both aldosterone and PAI-1 seem to promote cardiovascular (CV) injury. Our objective was to determine the roles of PAI-1 and aldosterone in the development of myocardial and renal damage in a model with high Ang II and low nitric oxide (NO) availability, a pattern seen in patients with heart failure, diabetes mellitus, and arteriosclerosis.
Mice on a moderately high sodium diet were treated with the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME) for 14 days plus Ang II during days 8 through 14. The roles of aldosterone and PAI-1 in the development of CV injury were assessed using the mineralocorticoid receptor antagonist spironolactone (0, 1.5, 15, and 50 mg x 100 g(-1) x day(-1)) and PAI-1-deficient mice (PAI-1-/-). Ang II/L-NAME-treated mice showed glomerular ischemia, proteinuria, and necrosis of myocytes and vascular smooth muscle cells with an associated mixed inflammatory response, deposition of loose collagen, and neovascularization. Compared with saline-drinking mice, Ang II/L-NAME-treated mice had significantly increased heart to body weight (HW/BW) ratios, cardiac and renal damage assessed by histological examination, PAI-1 immunoreactivity, and proteinuria. Spironolactone treatment decreased PAI-1 immunoreactivity and reduced in a dose-dependent fashion cardiac and renal damage. PAI-1-/- animals had a similar degree of CV injury as PAI-1+/+ animals.
Mineralocorticoid receptor antagonism, but not PAI-1 deficiency, protected mice from developing Ang II/L-NAME-mediated myocardial and vascular injury and proteinuria, suggesting that aldosterone, but not PAI-1, plays a key role in the development of early Ang II/L-NAME-induced cardiovascular injury.

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    ABSTRACT: The steroid hormone aldosterone regulates sodium and potassium homeostasis. Aldosterone and activation of the mineralocorticoid receptor also causes inflammation and fibrosis of the heart, fibrosis and remodelling of blood vessels and tubulointerstitial fibrosis and glomerular injury in the kidney. Aldosterone and mineralocorticoid-receptor activation initiate an inflammatory response by increasing the generation of reactive oxygen species by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria. High salt intake potentiates these effects, in part by activating the Rho family member Rac1, a regulatory subunit of reduced NADPH oxidase that activates the mineralocorticoid receptor. Studies in mice in which the mineralocorticoid receptor has been deleted from specific cell types suggest a key role for macrophages in promoting inflammation and fibrosis. Aldosterone can exert mineralocorticoid-receptor-independent effects via the angiotensin II receptor and via G-protein-coupled receptor 30. Mineralocorticoid-receptor antagonists are associated with decreased mortality in patients with heart disease and show promise in patients with kidney injury, but can elevate serum potassium concentration. Studies in rodents genetically deficient in aldosterone synthase or treated with a pharmacological aldosterone-synthase inhibitor are providing insight into the relative contribution of aldosterone compared with the contribution of mineralocorticoid-receptor activation in inflammation, fibrosis, and injury. Aldosterone-synthase inhibitors are under development in humans.
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