Elevated levels of plasminogen-activator inhibitor type 1 in atherosclerotic aorta

Paula K Shireman, W. J. McCarthy, W. H. Pearce, B. K. Patterson, V. P. Shively, M. Cipollone, N. Tamarina, E. N. Verrusio, H. C. Kwaan, H. P. Greisler

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Purpose: Plasminogen activator inhibitor type 1 (PAI-1) inhibits the plasminogen activators that convert plasminogen to plasmin. In addition to initiating fibrinolysis, plasmin activates tissue matrix metalloproteinases, which cause degradation of the extracellular matrix (ECM) in the arterial wall. Elevated levels of PAI-1 ultimately decrease plasmin formation and may lead to an accumulation of ECM and arteriosclerosis. Methods: PAI-1 was studied by four methods in atherosclerotic (aneurysmal and occlusive) and normal (organ donor) aorta: (1) PAI-1 secretion by tissue explant supernatants, including time course and inhibition studies; (2) tissue PAI-1 by protein extraction; (3) PAI-1 mRNA was quantitated by Northern analysis using glyceraldehyde-3-phosphate dehydrogenase to normalize for RNA loading; and (4) in situ hybridization was used to localize the cells that produced PAI-1 mRNA. Results: Supernatant PAI-1 levels at 48 hours were 776 ± 352 ng/ml in 11 atherosclerotic aortas and 248 ± 98 ng/ml in 8 normal aortas (p < 0.005). Tissue PAI-1 levels per 100 mg of tissue were 99 ± 58 ng in 11 atherosclerotic aortas and 38 ± 20 ng in 5 normal aortas (p < 0.05). PAI-1 mRNA levels by Northern analysis were 0.91 ± 0.49 in seven atherosclerotic aortas and 0.44 ± 0.27 in five normal aortas. Supernatant time-course experiments revealed that PAI-1 increased over time. Inhibitor studies revealed that PAI-1 decreased to approximately one third of control values when cycloheximide or actinomycin D were added to the media, indicating that active synthesis of PAI-1 had occurred. In-situ hybridization localized PAI- 1 mRNA predominately to endothelial cells and a few scattered vascular smooth muscle and inflammatory cells. Subgroup analysis revealed no statistically significant differences between aneurysmal and occlusive PAI-1 levels in any of the experiments. Conclusion: PAI-1 secretion, as measured by tissue explant supernatants, and total tissue PAI-1 in the protein extracts were significantly increased in atherosclerotic aorta. This elevation was also observed in the mRNA, which suggests that the increase is controlled at the level of transcription. PAI-1 mRNA was localized to endothelial, vascular smooth muscle, and inflammatory cells. We conclude that elevated levels of PAI-1 exist in diseased aorta. These elevated levels may lead to an accumulation of ECM, thereby contributing to the arteriosclerosis found in aortic occlusive and aneurysmal disease.

Original languageEnglish (US)
Pages (from-to)810-818
Number of pages9
JournalJournal of Vascular Surgery
Volume23
Issue number5
DOIs
StatePublished - 1996
Externally publishedYes

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Plasminogen Activator Inhibitor 1
Aorta
Messenger RNA
Fibrinolysin
Tissue Plasminogen Activator
Extracellular Matrix
Arteriosclerosis
Vascular Smooth Muscle
Smooth Muscle Myocytes
In Situ Hybridization
Replication Protein C
Glyceraldehyde-3-Phosphate Dehydrogenases
Plasminogen Activators
Plasminogen
Dactinomycin
Fibrinolysis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Shireman, P. K., McCarthy, W. J., Pearce, W. H., Patterson, B. K., Shively, V. P., Cipollone, M., ... Greisler, H. P. (1996). Elevated levels of plasminogen-activator inhibitor type 1 in atherosclerotic aorta. Journal of Vascular Surgery, 23(5), 810-818. https://doi.org/10.1016/S0741-5214(96)70243-4

Elevated levels of plasminogen-activator inhibitor type 1 in atherosclerotic aorta. / Shireman, Paula K; McCarthy, W. J.; Pearce, W. H.; Patterson, B. K.; Shively, V. P.; Cipollone, M.; Tamarina, N.; Verrusio, E. N.; Kwaan, H. C.; Greisler, H. P.

In: Journal of Vascular Surgery, Vol. 23, No. 5, 1996, p. 810-818.

Research output: Contribution to journalArticle

Shireman, PK, McCarthy, WJ, Pearce, WH, Patterson, BK, Shively, VP, Cipollone, M, Tamarina, N, Verrusio, EN, Kwaan, HC & Greisler, HP 1996, 'Elevated levels of plasminogen-activator inhibitor type 1 in atherosclerotic aorta', Journal of Vascular Surgery, vol. 23, no. 5, pp. 810-818. https://doi.org/10.1016/S0741-5214(96)70243-4
Shireman, Paula K ; McCarthy, W. J. ; Pearce, W. H. ; Patterson, B. K. ; Shively, V. P. ; Cipollone, M. ; Tamarina, N. ; Verrusio, E. N. ; Kwaan, H. C. ; Greisler, H. P. / Elevated levels of plasminogen-activator inhibitor type 1 in atherosclerotic aorta. In: Journal of Vascular Surgery. 1996 ; Vol. 23, No. 5. pp. 810-818.
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abstract = "Purpose: Plasminogen activator inhibitor type 1 (PAI-1) inhibits the plasminogen activators that convert plasminogen to plasmin. In addition to initiating fibrinolysis, plasmin activates tissue matrix metalloproteinases, which cause degradation of the extracellular matrix (ECM) in the arterial wall. Elevated levels of PAI-1 ultimately decrease plasmin formation and may lead to an accumulation of ECM and arteriosclerosis. Methods: PAI-1 was studied by four methods in atherosclerotic (aneurysmal and occlusive) and normal (organ donor) aorta: (1) PAI-1 secretion by tissue explant supernatants, including time course and inhibition studies; (2) tissue PAI-1 by protein extraction; (3) PAI-1 mRNA was quantitated by Northern analysis using glyceraldehyde-3-phosphate dehydrogenase to normalize for RNA loading; and (4) in situ hybridization was used to localize the cells that produced PAI-1 mRNA. Results: Supernatant PAI-1 levels at 48 hours were 776 ± 352 ng/ml in 11 atherosclerotic aortas and 248 ± 98 ng/ml in 8 normal aortas (p < 0.005). Tissue PAI-1 levels per 100 mg of tissue were 99 ± 58 ng in 11 atherosclerotic aortas and 38 ± 20 ng in 5 normal aortas (p < 0.05). PAI-1 mRNA levels by Northern analysis were 0.91 ± 0.49 in seven atherosclerotic aortas and 0.44 ± 0.27 in five normal aortas. Supernatant time-course experiments revealed that PAI-1 increased over time. Inhibitor studies revealed that PAI-1 decreased to approximately one third of control values when cycloheximide or actinomycin D were added to the media, indicating that active synthesis of PAI-1 had occurred. In-situ hybridization localized PAI- 1 mRNA predominately to endothelial cells and a few scattered vascular smooth muscle and inflammatory cells. Subgroup analysis revealed no statistically significant differences between aneurysmal and occlusive PAI-1 levels in any of the experiments. Conclusion: PAI-1 secretion, as measured by tissue explant supernatants, and total tissue PAI-1 in the protein extracts were significantly increased in atherosclerotic aorta. This elevation was also observed in the mRNA, which suggests that the increase is controlled at the level of transcription. PAI-1 mRNA was localized to endothelial, vascular smooth muscle, and inflammatory cells. We conclude that elevated levels of PAI-1 exist in diseased aorta. These elevated levels may lead to an accumulation of ECM, thereby contributing to the arteriosclerosis found in aortic occlusive and aneurysmal disease.",
author = "Shireman, {Paula K} and McCarthy, {W. J.} and Pearce, {W. H.} and Patterson, {B. K.} and Shively, {V. P.} and M. Cipollone and N. Tamarina and Verrusio, {E. N.} and Kwaan, {H. C.} and Greisler, {H. P.}",
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T1 - Elevated levels of plasminogen-activator inhibitor type 1 in atherosclerotic aorta

AU - Shireman, Paula K

AU - McCarthy, W. J.

AU - Pearce, W. H.

AU - Patterson, B. K.

AU - Shively, V. P.

AU - Cipollone, M.

AU - Tamarina, N.

AU - Verrusio, E. N.

AU - Kwaan, H. C.

AU - Greisler, H. P.

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N2 - Purpose: Plasminogen activator inhibitor type 1 (PAI-1) inhibits the plasminogen activators that convert plasminogen to plasmin. In addition to initiating fibrinolysis, plasmin activates tissue matrix metalloproteinases, which cause degradation of the extracellular matrix (ECM) in the arterial wall. Elevated levels of PAI-1 ultimately decrease plasmin formation and may lead to an accumulation of ECM and arteriosclerosis. Methods: PAI-1 was studied by four methods in atherosclerotic (aneurysmal and occlusive) and normal (organ donor) aorta: (1) PAI-1 secretion by tissue explant supernatants, including time course and inhibition studies; (2) tissue PAI-1 by protein extraction; (3) PAI-1 mRNA was quantitated by Northern analysis using glyceraldehyde-3-phosphate dehydrogenase to normalize for RNA loading; and (4) in situ hybridization was used to localize the cells that produced PAI-1 mRNA. Results: Supernatant PAI-1 levels at 48 hours were 776 ± 352 ng/ml in 11 atherosclerotic aortas and 248 ± 98 ng/ml in 8 normal aortas (p < 0.005). Tissue PAI-1 levels per 100 mg of tissue were 99 ± 58 ng in 11 atherosclerotic aortas and 38 ± 20 ng in 5 normal aortas (p < 0.05). PAI-1 mRNA levels by Northern analysis were 0.91 ± 0.49 in seven atherosclerotic aortas and 0.44 ± 0.27 in five normal aortas. Supernatant time-course experiments revealed that PAI-1 increased over time. Inhibitor studies revealed that PAI-1 decreased to approximately one third of control values when cycloheximide or actinomycin D were added to the media, indicating that active synthesis of PAI-1 had occurred. In-situ hybridization localized PAI- 1 mRNA predominately to endothelial cells and a few scattered vascular smooth muscle and inflammatory cells. Subgroup analysis revealed no statistically significant differences between aneurysmal and occlusive PAI-1 levels in any of the experiments. Conclusion: PAI-1 secretion, as measured by tissue explant supernatants, and total tissue PAI-1 in the protein extracts were significantly increased in atherosclerotic aorta. This elevation was also observed in the mRNA, which suggests that the increase is controlled at the level of transcription. PAI-1 mRNA was localized to endothelial, vascular smooth muscle, and inflammatory cells. We conclude that elevated levels of PAI-1 exist in diseased aorta. These elevated levels may lead to an accumulation of ECM, thereby contributing to the arteriosclerosis found in aortic occlusive and aneurysmal disease.

AB - Purpose: Plasminogen activator inhibitor type 1 (PAI-1) inhibits the plasminogen activators that convert plasminogen to plasmin. In addition to initiating fibrinolysis, plasmin activates tissue matrix metalloproteinases, which cause degradation of the extracellular matrix (ECM) in the arterial wall. Elevated levels of PAI-1 ultimately decrease plasmin formation and may lead to an accumulation of ECM and arteriosclerosis. Methods: PAI-1 was studied by four methods in atherosclerotic (aneurysmal and occlusive) and normal (organ donor) aorta: (1) PAI-1 secretion by tissue explant supernatants, including time course and inhibition studies; (2) tissue PAI-1 by protein extraction; (3) PAI-1 mRNA was quantitated by Northern analysis using glyceraldehyde-3-phosphate dehydrogenase to normalize for RNA loading; and (4) in situ hybridization was used to localize the cells that produced PAI-1 mRNA. Results: Supernatant PAI-1 levels at 48 hours were 776 ± 352 ng/ml in 11 atherosclerotic aortas and 248 ± 98 ng/ml in 8 normal aortas (p < 0.005). Tissue PAI-1 levels per 100 mg of tissue were 99 ± 58 ng in 11 atherosclerotic aortas and 38 ± 20 ng in 5 normal aortas (p < 0.05). PAI-1 mRNA levels by Northern analysis were 0.91 ± 0.49 in seven atherosclerotic aortas and 0.44 ± 0.27 in five normal aortas. Supernatant time-course experiments revealed that PAI-1 increased over time. Inhibitor studies revealed that PAI-1 decreased to approximately one third of control values when cycloheximide or actinomycin D were added to the media, indicating that active synthesis of PAI-1 had occurred. In-situ hybridization localized PAI- 1 mRNA predominately to endothelial cells and a few scattered vascular smooth muscle and inflammatory cells. Subgroup analysis revealed no statistically significant differences between aneurysmal and occlusive PAI-1 levels in any of the experiments. Conclusion: PAI-1 secretion, as measured by tissue explant supernatants, and total tissue PAI-1 in the protein extracts were significantly increased in atherosclerotic aorta. This elevation was also observed in the mRNA, which suggests that the increase is controlled at the level of transcription. PAI-1 mRNA was localized to endothelial, vascular smooth muscle, and inflammatory cells. We conclude that elevated levels of PAI-1 exist in diseased aorta. These elevated levels may lead to an accumulation of ECM, thereby contributing to the arteriosclerosis found in aortic occlusive and aneurysmal disease.

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