Plasminogen Activator Inhibitor-1 Is a Major Determinant of Arterial Thrombolysis Resistance

Zhu, Yanhong; Carmeliet, Peter; Fay, William P.

doi:10.1161/01.cir.99.23.3050

Cited by 168 publications

(130 citation statements)

References 40 publications

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“…2,3 Coronary microvascular dysfunction is caused not only by traditional risk factors such as hypertension, hyperlipidemia, diabetes mellitus, and smoking, but also by various atherogenic factors such as inflammation, oxidative stress, and thrombosis. [4][5][6][7] Plasminogen activator inhibitor-1 (PAI-1), a fast-acting inhibitor of plasminogen activation, is produced by the vascular endothelium, but is also present in platelets and is considered to be an important regulator of fibrinolysis. 5,8 Elevated plasma PAI-1 activity has been demonstrated to be associated with the impairment of flowmediated dilatation, vessel wall thickening, and vascular wall stress.…”

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confidence: 99%

“…[4][5][6][7] Plasminogen activator inhibitor-1 (PAI-1), a fast-acting inhibitor of plasminogen activation, is produced by the vascular endothelium, but is also present in platelets and is considered to be an important regulator of fibrinolysis. 5,8 Elevated plasma PAI-1 activity has been demonstrated to be associated with the impairment of flowmediated dilatation, vessel wall thickening, and vascular wall stress. [9][10][11][12] Elevated plasma PAI-1 activity was also related to the intima -media thickness of carotid arteries in a cross-sectional case -control study.…”

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confidence: 99%

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Elevated Plasma Plasminogen Activator Inhibitor Type-1 is an Independent Predictor of Coronary Microvascular Dysfunction in Hypertension

Naya

Tsukamoto

Inubushi

et al. 2007

Circ J

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Background Elevated plasma plasminogen activator inhibitor-1 (PAI-1) is related to cardiovascular events, but its role in subclinical coronary microvascular dysfunction remains unknown. Thus, in the present study it was investigated whether elevated plasma PAI-1 activity is associated with coronary microvascular dysfunction in hypertensive patients. Methods and ResultsThirty patients with untreated essential hypertension and 10 age-matched healthy controls were studied prospectively. Myocardial blood flow (MBF) was measured by using 15 O-water positron emission tomography. Clinical variables associated with atherosclerosis (low-density lipoprotein-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, homeostasis model assessment (HOMA-IR), and PAI-1 activity) were assessed to determine their involvement in coronary microvascular dysfunction. Adenosine triphosphate (ATP)-induced hyperemic MBF and coronary flow reserve (CFR) were significantly lower in hypertensive patients than in healthy controls (ATP-induced MBF: 2.77±0.82 vs 3.49±0.71 ml·g -1 ·min -1 ; p<0.02 and CFR: 2.95±1.06 vs 4.25±0.69; p<0.001). By univariate analysis, CFR was positively correlated with HDL-cholesterol (r=0.46, p<0.02), and inversely with HOMA-IR (r=-0.39, p<0.05) and PAI-1 activity (r=-0.61, p<0.001). By multivariate analysis, elevated PAI-1 activity remained a significant independent determinant of diminished CFR. Conclusions Elevated plasma PAI-1 activity was independently associated with coronary microvascular dysfunction, which suggests that plasma PAI-1 activity is an important clue linking hypofibrinolysis to the development of atherosclerosis. (Circ J 2007; 71: 348 -353)

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confidence: 99%

Elevated Plasma Plasminogen Activator Inhibitor Type-1 is an Independent Predictor of Coronary Microvascular Dysfunction in Hypertension

Naya

Tsukamoto

Inubushi

et al. 2007

Circ J

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“…Some of the treated patients will suffer from reocclusion or bleeding complications such as hemorrhagic strokes (2,3,6). Furthermore, the reoccluded clots are usually platelet-rich and are more resistant to tPA-mediated clot lysis (7,8). Hence, choices of more potent blood clot dissolving agents, which provide a rapid, complete, and sustained reperfusion with minimal side effects, are needed.…”

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confidence: 99%

A Fast-acting, Modular-structured Staphylokinase Fusion with Kringle-1 from Human Plasminogen as the Fibrin-targeting Domain Offers Improved Clot Lysis Efficacy

Wong

2003

Journal of Biological Chemistry

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To develop a fast-acting clot dissolving agent, a clottargeting domain derived from the Kringle-1 domain in human plasminogen was fused to the C-terminal end of staphylokinase with a linker sequence in between. Production of this fusion protein in Bacillus subtilis and Pichia pastoris was examined. The Kringle domain in the fusion protein produced from B. subtilis was improperly folded because of its complicated disulfidebond profile, whereas the staphylokinase domain produced from P. pastoris was only partially active because of an N-linked glycosylation. A change of the glycosylation residue, Thr-30, to alanine resulted in a non-glycosylated biologically active fusion. The resulting mutein, designated SAKM3-L-K1, was overproduced in P. pastoris. Each domain in SAKM3-L-K1 was functional, and this fusion showed fibrin binding ability by binding directly to plasmin-digested clots. In vitro fibrin clot lysis in a static environment and plasma clot lysis in a flowcell system demonstrated that the engineered fusion outperformed the non-fused staphylokinase. The time required for 50% clot lysis was reduced by 20 to 500% under different conditions. Faster clot lysis can potentially reduce the degree of damage to occluded heart tissues.

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“…11 In plasma, PAI-1 is a critical determinant of endogenous fibrinolytic activity and resistance to thrombolysis. 12 In vascular tissue, PAI-1 influences the response to injury by impairing cellular migration 13 and matrix degradation. 14 There is substantial evidence that PAI-1 may contribute to the development of fibrosis and/or sclerosis after chemical 15 or ionizing 16 injury.…”

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Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition

et al. 2001

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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 (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 Ϫ/Ϫ ) and wild-type (WT) male mice (Nϭ6 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 141Ϯ3 mm Hg in WT animals versus 112Ϯ4 mm Hg in PAI-1 Ϫ/Ϫ mice (PϽ0.0001). The extent of coronary perivascular fibrosis increased significantly in L-NAME-treated WT mice (PϽ0.01 versus PAI-1 Ϫ/Ϫ mice). Cardiac type I collagen mRNA expression was greater in control (PϽ0.01) and L-NAME-treated PAI-1 Ϫ/Ϫ (PϽ0.05) 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.

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Plasminogen Activator Inhibitor-1 Is a Major Determinant of Arterial Thrombolysis Resistance

Cited by 168 publications

References 40 publications

Elevated Plasma Plasminogen Activator Inhibitor Type-1 is an Independent Predictor of Coronary Microvascular Dysfunction in Hypertension

Elevated Plasma Plasminogen Activator Inhibitor Type-1 is an Independent Predictor of Coronary Microvascular Dysfunction in Hypertension

A Fast-acting, Modular-structured Staphylokinase Fusion with Kringle-1 from Human Plasminogen as the Fibrin-targeting Domain Offers Improved Clot Lysis Efficacy

Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition

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