doi: 10.1161/hc3301.092803
(Circulation. 2001;104:839.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition
From the Departments of Medicine and Pharmacology (K.K., J.A.S., N.J.B., D.E.V.) and the Department of Pathology (K.K., A.B.F., L.M.), Vanderbilt University Medical Center, Nashville, Tenn.
Correspondence to Douglas E. Vaughan, MD, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave, Room 315, Nashville, TN 37232-6300A. E-mail doug.vaughan{at}mcmail.vanderbilt.edu
Background— Long-term inhibition of nitric oxide synthase (NOS) is known to induce hypertension and perivascular fibrosis. Recent evidence also suggests that long-term NOS inhibition induces expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues and that PAI-1 may contribute to the development of fibrosis after chemical or ionizing injury. On the basis of these observations, we hypothesized that PAI-1 may influence the vascular response to long-term NOS inhibition by N
-nitro-L-arginine methyl ester (L-NAME).
Methods and Results— We compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis in PAI-1–deficient (PAI-1-/-) and wild-type (WT) male mice (N=6 per group). At baseline, there were no significant differences in blood pressure between groups. After initiation of L-NAME, systolic blood pressure increased in both groups at 2 weeks. Over an 8-week study period, systolic blood pressure increased to 141±3 mm Hg in WT animals versus 112±4 mm Hg in PAI-1-/- mice (P<0.0001). The extent of coronary perivascular fibrosis increased significantly in L-NAME–treated WT mice (P<0.01 versus PAI-1-/- mice). Cardiac type I collagen mRNA expression was greater in control (P<0.01) and L-NAME–treated PAI-1-/- (P<0.05) groups than in control WT mice, indicating that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation.
Conclusions— These findings suggest that PAI-1 deficiency alone is sufficient to protect against the structural vascular changes that accompany hypertension in the setting of long-term NOS inhibition. Direct inhibition of vascular PAI-1 activity may provide a new therapeutic strategy for the prevention of arteriosclerotic cardiovascular disease.
Key Words: nitric oxide synthase • plasminogen activators • hypertension • collagen
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