Aldosterone activates endothelial exocytosis.

Although elevated levels of aldosterone are associated with vascular inflammation, the proinflammatory pathways of aldosterone are not completely defined. We now show that aldosterone triggers endothelial cell exocytosis, the first step in leukocyte trafficking. Exogenous aldosterone stimulates endothelial exocytosis of Weibel-Palade bodies, externalizing P-selectin and releasing von Willebrand factor. Spironolactone, a nonselective mineralocorticoid receptor (MR) blocker, antagonizes aldosterone-induced endothelial exocytosis. Knockdown of the MR also decreases exocytosis, suggesting that the MR mediates exocytosis. Aldosterone triggers exocytosis within minutes, and this effect is not inhibited by actinomycin D, suggesting a nongenomic effect of aldosterone. Aldosterone treatment of endothelial cells increases leukocyte adherence to endothelial cells in culture. Taken together, our data suggest that aldosterone activates vascular inflammation in part through nongenomic, MR-mediated pathways. Aldosterone antagonism may decrease vascular inflammation and cardiac fibrosis in part by blocking endothelial exocytosis.

Heart failure and greater infarct expansion in middle-aged mice: a relevant model for postinfarction failure.

Young mice tolerate myocardial loss after coronary artery ligation (CAL) without congestive heart failure (CHF) signs or mortality. We predicted a CHF phenotype after CAL in aged mice. Left coronary artery ligation produced permanent myocardial infarcts (MI). Mortality was higher in male 14-mo-old C57BL/6N mice (Older mice) than in 2-mo-old mice (Young mice) (16 of 25 Older mice died vs. 0 of 10 Young mice, P < 0.02). After 8 wk, rales, weight loss, and lethargy preceded deaths. Captopril (50 mg x kg(-1) x day(-1)) increased Older mouse survival (6 of 22 died, P < 0.02). Captopril improved systolic function (peak aortic blood velocity) from 76 +/- 6% of baseline in untreated Older mice to 93 +/- 8% (P < 0.036). At 24 h, MI comprised 28 +/- 4% of the left ventricle in Young mice, surprisingly larger than that in Older mice (18 +/- 2%, P < 0.011). Endocardial area underlying the infarct scar was significantly larger in Older mice than in Young mice. Captopril did not reduce expansion but markedly reduced septal hypertrophy. Aging reduces compensatory ability in mice despite smaller acute infarcts. Less effective myocardial repair, greater infarct expansion, and septal hypertrophy are seen with aging. Aging is a more relevant murine model of post-MI heart failure in patients.