Angiotensin-Converting Enzyme Inhibitor Prevents Plasminogen Activator Inhibitor-1 Expression in a Rat Model with Cardiovascular Remodeling Induced by Chronic Inhibition of Nitric Oxide Synthesis

M. Katoh, K. Egashira, T. Mitsui, S. Chishima, A. Takeshita and H. Narita. Angiotensin-Converting Enzyme Inhibitor Prevents Plasminogen Activator Inhibitor-1 Expression in a Rat Model with Cardiovascular Remodeling Induced by Chronic Inhibition of Nitric Oxide Synthesis. Journal of Molecular and Cellular Cardiology (2000) 32, 73–83. Plasminogen activator inhibitor-1 (PAI-1) may participate in the development of cardiovascular remodeling by inhibiting extracellular matrix turnover and fibrinolysis. However, little is known about physiological regulators of PAI-1 in vivo. Angiotensin II has been shown to stimulate PAI-1 in vitro. We previously reported that long-term inhibition of nitric oxide (NO) synthesis with Nω-nitro-L-arginine methyl ester (L-NAME) causes cardiovascular remodeling (vascular medial thickening and fibrosis) associated with increased tissue angiotensin-converting enzyme (ACE) activity. In the present study, we examined whether treatment with an ACE inhibitor modulates the cardiovascular PAI-1 expression in this model in vivo. Wistar–Kyoto rats were treated with either no drugs, L-NAME (100 mg/kg•day), or L-NAME plus the ACE inhibitor imidapril (20 mg/kg day). Marked increases in PAI-1 mRNA and protein levels in the aorta and left ventricle were observed after the first and fourth weeks of PAI-1 treatment. PAI-1 immunoreactivity was increased in the endothelium and the media of the aorta and coronary arteries after treatment of L-NAME. This increase in PAI-1 levels was associated with an increase in ACE activity of the aorta and left ventricle. ACE inhibition with imidapril significantly prevented both the increases in PAI-1 levels and the development of cardiovascular remodeling. These findings suggest that the local renin–angiotensin system regulates PAI-1 expression, and that the increased PAI-1 levels may contribute to the cardiovascular remodeling in this model.