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

Author： Katoh M. Egashira K. Mitsui T. Chishima S. Takeshita A. Narita H.

Publisher： Academic Press

ISSN： 0022-2828

Source： Journal of Molecular and Cellular Cardiology, Vol.32, Iss.1, 2000-01, pp. : 73-83

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Abstract

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 N&ohgr;-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.