Dose-dependent limitation of arterial enlargement by the matrix metalloproteinase inhibitor RS-113,4561

John K Karwowski, Amy Markezich, Jared Whitson, Thomas A. Abbruzzese, Christopher K. Zarins, Ronald L. Dalman

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Background. Arterial diameter changes in response to flow. Chronic flow- mediated arterial enlargement may be mediated through metalloproteinase activity in the extracellular matrix of the arterial wall. We examined flow- mediated enlargement in the setting of increasing competitive matrix metalloproteinase (MMP) inhibition and with respect to gelatinase A and B expression and activity. Methods. Left common femoral arteriovenous fistulas (AVFs) were created in dose-response (52) and time course (34) cohorts of rats. Dose-response rats received either vehicle alone or 12.5, 25, or 37.5 mg/kg b.i.d. RS 113,456, a competitive MMP inhibitor. Heart rate, blood pressure, and weight were measured at intervals following AVF construction. Aortic and common iliac diameters were measured on postoperative day (POD) 21. Untreated time course rats were sacrificed on PODs 0 (no AVF), 3, 7, 14, and 21. Aortic diameter was measured and the vessels were harvested for tissue analysis. Equal amounts of aortic RNA underwent reverse transcription and polymerase chain reaction with primers for MMP-2, MMP-9, and GAPDH. Zymography was performed on iliac artery tissue to measure gelatinolytic activity. Results. A significant, stepwise reduction in flow-mediated aortic and left common iliac enlargement following left femoral AVF creation was noted with progressively higher doses of RS 113,456 without apparent hemodynamic or toxic effects. Right common iliac diameter was unchanged. Over 21 days following AVF creation, there was an upward trend in expression and activity for MMP-2 not evident for MMP-9. Conclusion. Flow-mediated arterial enlargement is limited by competitive MMP inhibition in a dose-dependent fashion. MMP-dependent flow-mediated enlargement may involve differential expression and activity of MMP-2 and MMP-9.

Original languageEnglish (US)
Pages (from-to)122-129
Number of pages8
JournalJournal of Surgical Research
Volume87
Issue number1
DOIs
StatePublished - Nov 1999
Externally publishedYes

Fingerprint

Matrix Metalloproteinase Inhibitors
Arteriovenous Fistula
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Matrix Metalloproteinases
Thigh
Iliac Artery
Poisons
Metalloproteases
Reverse Transcription
Extracellular Matrix
Heart Rate
Hemodynamics
RNA
Blood Pressure
Weights and Measures
Polymerase Chain Reaction

Keywords

  • 72-kDa gelatinase A
  • 92-kDa gelatinase B
  • Arterial remodeling
  • Dose response
  • Extracellular matrix
  • Matrix metalloproteinases

ASJC Scopus subject areas

  • Surgery

Cite this

Karwowski, J. K., Markezich, A., Whitson, J., Abbruzzese, T. A., Zarins, C. K., & Dalman, R. L. (1999). Dose-dependent limitation of arterial enlargement by the matrix metalloproteinase inhibitor RS-113,4561. Journal of Surgical Research, 87(1), 122-129. https://doi.org/10.1006/jsre.1999.5707

Dose-dependent limitation of arterial enlargement by the matrix metalloproteinase inhibitor RS-113,4561. / Karwowski, John K; Markezich, Amy; Whitson, Jared; Abbruzzese, Thomas A.; Zarins, Christopher K.; Dalman, Ronald L.

In: Journal of Surgical Research, Vol. 87, No. 1, 11.1999, p. 122-129.

Research output: Contribution to journalArticle

Karwowski, JK, Markezich, A, Whitson, J, Abbruzzese, TA, Zarins, CK & Dalman, RL 1999, 'Dose-dependent limitation of arterial enlargement by the matrix metalloproteinase inhibitor RS-113,4561', Journal of Surgical Research, vol. 87, no. 1, pp. 122-129. https://doi.org/10.1006/jsre.1999.5707
Karwowski, John K ; Markezich, Amy ; Whitson, Jared ; Abbruzzese, Thomas A. ; Zarins, Christopher K. ; Dalman, Ronald L. / Dose-dependent limitation of arterial enlargement by the matrix metalloproteinase inhibitor RS-113,4561. In: Journal of Surgical Research. 1999 ; Vol. 87, No. 1. pp. 122-129.
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abstract = "Background. Arterial diameter changes in response to flow. Chronic flow- mediated arterial enlargement may be mediated through metalloproteinase activity in the extracellular matrix of the arterial wall. We examined flow- mediated enlargement in the setting of increasing competitive matrix metalloproteinase (MMP) inhibition and with respect to gelatinase A and B expression and activity. Methods. Left common femoral arteriovenous fistulas (AVFs) were created in dose-response (52) and time course (34) cohorts of rats. Dose-response rats received either vehicle alone or 12.5, 25, or 37.5 mg/kg b.i.d. RS 113,456, a competitive MMP inhibitor. Heart rate, blood pressure, and weight were measured at intervals following AVF construction. Aortic and common iliac diameters were measured on postoperative day (POD) 21. Untreated time course rats were sacrificed on PODs 0 (no AVF), 3, 7, 14, and 21. Aortic diameter was measured and the vessels were harvested for tissue analysis. Equal amounts of aortic RNA underwent reverse transcription and polymerase chain reaction with primers for MMP-2, MMP-9, and GAPDH. Zymography was performed on iliac artery tissue to measure gelatinolytic activity. Results. A significant, stepwise reduction in flow-mediated aortic and left common iliac enlargement following left femoral AVF creation was noted with progressively higher doses of RS 113,456 without apparent hemodynamic or toxic effects. Right common iliac diameter was unchanged. Over 21 days following AVF creation, there was an upward trend in expression and activity for MMP-2 not evident for MMP-9. Conclusion. Flow-mediated arterial enlargement is limited by competitive MMP inhibition in a dose-dependent fashion. MMP-dependent flow-mediated enlargement may involve differential expression and activity of MMP-2 and MMP-9.",
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