Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition

K Kaikita, AB Fogo, L Ma, JA Schoenhard, NJ Brown… - Circulation, 2001 - Am Heart Assoc
K Kaikita, AB Fogo, L Ma, JA Schoenhard, NJ Brown, DE Vaughan
Circulation, 2001Am Heart Assoc
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 Nω-nitro-l-arginine methyl ester (L-NAME) …
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 Nω-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.
Am Heart Assoc