Published online before print October 27, 2003, doi: 10.1161/01.CIR.0000097000.51723.6F
(Circulation. 2003;108:2517.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Aldosterone and Not Plasminogen Activator Inhibitor-1 Is a Critical Mediator of Early Angiotensin II/NG-Nitro-L-Arginine Methyl Ester-Induced Myocardial Injury
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.
Correspondence to Gail K. Adler, MD, PhD, Division of Endocrinology, Hypertension and Diabetes, Brigham and Women’s Hospital, 221 Longwood Ave, Boston, MA 02115. E-mail gadler{at}partners.org
Received March 31, 2003; de novo received June 13, 2003; revision received July 16, 2003; accepted July 23, 2003.
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.
Key Words: plasminogen activator inhibitor • angiotensin • myocardium • kidney
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