O-21: Aldosterone/salt-induced myocardial injury: A vascular inflammatory disease

• Published in: American journal of hypertension Vol. 14; no. S1; pp. 8A - 9A
• Main Authors: Blasi, Eileen R., Frierdrich, Gregory E., De Ciechi, Pamela A., Coughenour, Marvin A., Amy, Rudolph E., McMahon, Ellen G., Rocha, Ricardo
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2001
• Subjects: aldosterone; COX-2; vascular inflammation
• DOI: 10.1016/S0895-7061(01)01338-3
• ISSN: 0895-7061

We have examined the early pathophysiologic and molecular events associated to the development of aldosterone-induced myocardial disease. Uninephrectomized, saline-drinking, Sprage-Dawley rats (250g, n=48) were fitted with osmotic mini-pumps containing either aldosterone (0.75 micro gr/hr, s.c., ALDO) or vehicle (VEH). Previous studies showed that this treatment induces myocardial hypertrophy and fibrosis after 6 to 8 weeks. Radio-telemetric determination of blood pressure over 28 days evidenced the progressive development of hypertension in ALDO-infused (systolic: 230 mmHg) vs. VEH-treated rats (systolic: 134 mmHg, P<.001). Six animals from each group were sacrificed after 3, 7, 14 or 28 days of infusion. Histopathologic examination of the hearts showed the presence of biventricular, perivascular inflammatory infiltrates in 4 of the 6 animals infused with aldosterone for 7 days and in all rats receiving ALDO for 14 or 28 days. The lesions compromised primarily medium and small-sized coronary arteries. The perivascular inflammatory cells were identified as mainly macrophages (ED1 staining) and were associated in some cases with fibrinoid necrosis of the media. Cardiomyocyte necrosis was observed only in areas of extensive vascular inflammation and progressed in frequency and severity with time. No lesions were observed in animals infused with either VEH or ALDO for only 3 days. Morphometric determination of interstitial collagen volume fraction or perivascular collagen did not show significant increases in response to ALDO treatment at these early time-points. Progressive pathophysiology was profiled using gene microarray analysis and over 500 genes demonstrated significant differential expression with ALDO compared to VEH. RT-PCR analysis demonstrated a statistically significant (P<.05) ALDO-induced upregulation of the expression of ANP (27.9-fold), BNP (3.0-fold), myosin heavy chain-β (3.7-fold), and endothelin-1 (2.8-fold), and a significant decrease in the gene expression of myosin heavy chain-α compared to VEH. In addition, upregulation of the inflammatory mediator COX-2 (4.3-fold, P<.05) and the cytokine osteopontin (15.5-fold, P<.01) were identified in ALDO-treated rats. Immunohistochemical analysis identified the presence of these two molecules in the media and adventitia of coronary arteries starting at day 7 of ALDO infusion. Thus, we identified vascular inflammation as a pivotal early event in the onset and progression of aldosterone/NaCl-induced myocardial disease with COX-2 and osteopontin as potential mediators of this process. Other Financial or Material Support - Pharmacia Corp.