Journal
CIRCULATION
Volume 104, Issue 7, Pages 839-844Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hc3301.092803
Keywords
nitric oxide synthase; plasminogen activators; hypertension; collagen
Funding
- NIGMS NIH HHS [T32-GM-07437-22] Funding Source: Medline
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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 (PAM) 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-omega -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 nun Hg in WT animals versus 112 +/-4 min Hg in PAL-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 PAM 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.
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