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


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 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.


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.
Division of Endocrinology, Hypertension and Diabetes, Department of Medicine, Brigham and Women's Hospital, 221 Longwood Ave, Boston, Mass 02115, USA.
Eveline M
EM
Oestreicher
Diego
D
Martinez-Vasquez
James R
JR
Stone
Larus
L
Jonasson
Weranuj
W
Roubsanthisuk
Koji
K
Mukasa
Gail K
GK
Adler
D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II; D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D003324:Coronary Artery Disease / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011507:Proteinuria / Q000139:chemically induced / Q000517:prevention & control; D012982:Sodium, Dietary; D013148:Spironolactone / Q000494:pharmacology
D000451:Mineralocorticoid Receptor Antagonists; D017395:Plasminogen Activator Inhibitor 1; D012982:Sodium, Dietary; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D019331:NG-Nitroarginine Methyl Ester