Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition.
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(omega)-nitro-L-arginine methyl ester (L-NAME).


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.
Kaikita
K
K
Department of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA.
Fogo
A B
AB
Ma
L
L
Schoenhard
J A
JA
Brown
N J
NJ
Vaughan
D E
DE
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013995:Time
D004791:Enzyme Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D003094:Collagen; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester