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.
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 Nomega-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 x 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.
Katoh
M
M
Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd, Toda, Saitama, Japan.
Egashira
K
K
Mitsui
T
T
Chishima
S
S
Takeshita
A
A
Narita
H
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007124:Immunoenzyme Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000473:pathology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D011921:Rats, Inbred WKY; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D017395:Plasminogen Activator Inhibitor 1; D006830:Hydralazine; D009569:Nitric Oxide; C065166:imidapril; D007703:Peptidyl-Dipeptidase A; D010959:Tissue Plasminogen Activator; D019331:NG-Nitroarginine Methyl Ester