Losartan inhibits the angiotensin II-induced modifications on fibrinolysis and matrix deposition by primary human vascular smooth muscle cells.

Disorders in the fibrinolytic and renin-angiotensin-aldosterone systems and excessive extracellular matrix (ECM) deposition are determinant factors in several pathologic manifestations of vascular and cardiac tissue. We used primary human vascular smooth muscle cells (VSMC) and studied the effects of losartan on angiotensin II (Ang II)-mediated (a) DNA synthesis, (b) secretion of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), (c) secretion of matrix metalloprotease-2 (MMP-2) activity and tissue inhibitors of MMPs (TIMPs), and (d) synthesis of glycosaminoglycans. VSMC cultures, established from human pulmonary arteries, were treated with Ang II (0.1 nM -1 microM ) and/or losartan (0.1-10 microM ), for 24 or 48 h. DNA synthesis was assessed by incorporation of 3 H-thymidine into VSMC, secreted tPA, PAI-1, and TIMPs by enzyme-linked immunosorbent assay, MMP-2 activity by gelatin zymography, and glycosaminoglycan synthesis by 3 H-glucosamine incorporation. Ang II (1 microM ) enhanced DNA synthesis and secretion of PAI-1 and glycosaminoglycans and decreased secretion of MMP-2 activity and tPA, whereas it had no effect on secretion of TIMPs and glycosaminoglycans associated with cell layers. The Ang II-mediated effects were reversed by losartan, in a concentration-dependent manner. Losartan alone increased secretion of tPA, MMP-2 activity, and TIMPs and decreased secretion of PAI-1. These results indicate that AT 1 receptors are implicated in Ang II-mediated disorders of fibrinolysis and excessive ECM deposition by VSMC.