YIA 03-08 ALDOSTERONE INDUCES TIMP-1 EXPRESSION AND FURTHER CONTRIBUTES TO COLLAGEN ACCUMULATION: FROM CLINICAL TO BENCH STUDIES.

OBJECTIVE: Aldosterone induces myocardial fibrosis. The tissue inhibitor of metalloproteinases-1 (TIMP-1) is a key factor of myocardial fibrosis and diastolic dysfunction, but the effect of aldosterone on TIMP-1 expression remains unclear. We tested the hypothesis that aldosterone induces TIMP-1 expression and contributes to the fibrotic process.

DESIGN AND METHOD: In the human study, we prospectively enrolled 54 patients with primary aldosteronism. Plasma TIMP-1 and echocardiographic parameters were measured. In the cell study, we investigated the possible molecular mechanism of aldosterone to induce TIMP-1 secretion and the further effects on collagen accumulation in human cardiac fibroblasts. In the animal study, we measured serum TIMP-1 levels, cardiac TIMP-1 levels, and cardiac structure in aldosterone-infusion mouse models by aldosterone pellets implantation.

RESULTS: In PA patients, the plasma TIMP-1 concentration was positively correlated with 24-hour urinary aldosterone, left ventricular mass, and the impairment of left ventricular diastolic function. In human cardiac fibroblasts, TIMP-1 protein and mRNA expression was significantly increased by aldosterone. The intracellular signaling pathway occurred through the glucocorticoid receptor / PI3K/Akt/NF-kB pathway. In addition, we found that TIMP-1 small interfering RNA significantly reduced aldosterone-caused collagen accumulation. Meanwhile, aldosterone did not change collagen 1a1 or MMP-1 mRNA levels. However, the aldosterone-induced TIMP-1 expression was inversely related to MMP-1 activity. Furthermore, in the animal model, the serum and cardiac level of TIMP-1 was significantly elevated in the mice with aldosterone infusion. The elevation was blocked by RU-486 but not eplerenone; it suggests the effect was through glucocorticoid receptor. In a long-term aldosterone-infusion model, serum TIMP-1 was associated with serum aldosterone levels, cardiac structure and fibrosis.

CONCLUSIONS: Aldosterone induces TIMP-1 expression in vivo and in vitro. Aldosterone induces TIMP-1 expression via the glucocorticoid receptor, PI3K and NF-kB pathway in cardiac fibroblasts. This increased TIMP-1 expression resulted in enhanced collagen accumulation via the suppression of MMP-1 activity.