on October 27, 2003
Published online before print October 27, 2003, doi: 10.1161/01.CIR.0000097000.51723.6F
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Submitted on March 31, 2003
From the Division of Endocrinology, Diabetes and Hypertension, Department of Medicine (E.M.O., D.M.-V., W.R., K.M., G.K.A.), and Department of Pathology (J.R.S.), Brigham and Women’s Hospital, and Department of Pathology (L.J.), Beth Israel Deaconess Hospital and Harvard Medical School, Boston, Mass. * To whom correspondence should be addressed. E-mail: gadler{at}partners.org.
Background--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. Methods and Results--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 · 100 g-1 · 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. Conclusions--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.
Revised on July 16, 2003
Accepted on July 23, 2003
Aldosterone and Not Plasminogen Activator Inhibitor-1 Is a Critical Mediator of Early Angiotensin II/NG-Nitro-L-Arginine Methyl Ester-Induced Myocardial Injury
Eveline M. Oestreicher MD,
Key words: plasminogen activator inhibitor • angiotensin • myocardium • kidney
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