Losartan inhibits the angiotensin II-induced modifications on fibrinolysisand 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 o f losartan on angiotensin II (Ang II)-mediated (a) DNA synthesis, (b) secre tion of tissue-type plasminogen activator (tPA) and plasminogen activator i nhibitor-1 (PAI-1). (c) secretion of matrix metalloprotease-2 (MMP-2) activ ity and tissue inhibitors of MMPs (TIMPs), and (d) synthesis of glycosamino glycans. VSMC cultures, established from human pulmonary arteries, were tre ated with Ang II (0.1 nM-1 muM) and/or losartan (0.1-10 muM), for 24 or 48 h. DNA synthesis was assessed by incorporation of H-3-thymidine into VSMC, secreted tPA, PAI-1, and TIMPs by enzyme-linked immunosorbent assay, MMP-2 activity by gelatin zymography, and glycosaminoglycan synthesis by H-3-gluc osamine incorporation. Ang II (1 muM) enhanced DNA synthesis and secretion of PAI-1 and glycosaminoglycans and decreased secretion of MMP-2 activity a nd tPA, whereas it had no effect on secretion of TIMPs and glycosaminoglyca ns associated with cell layers. The Ang II-mediated effects were reversed b y losartan, in a concentration-dependent manner. Losartan alone increased s ecretion of tPA, MMP-2 activity, and TIMPs and decreased secretion of PAI-1 . These results indicate that AT, receptors are implicated in Ang II-mediat ed disorders of fibrinolysis and excessive ECM deposition by VSMC.