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Deleterious effects of lack of cardiac PAI-1 after coronary occlusion in mice and their pathophysiologic determinants

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Abstract

We sought to delineate mechanisms through which the lack of plasminogen activator inhibitor (PAI)-1 in the heart affects remodeling of the heart early after myocardial infarction (MI). MI was induced by coronary occlusion in 10-weeks old PAI-1 knockout (KO) and control mice. Three days after MI, systolic and diastolic function was assessed with high-resolution echocardiography, infarct size was determined biochemically and histologically and accumulation of acute inflammatory cells in zones of infarction was characterized by immunocytochemistry. PAI-1 KO mice exhibited markedly thickened diastolic left ventricular anterior walls (1.38 ± 0.38 mm vs. 0.77 ± 0.13 SD), more profound depression of global and regional cardiac function (19 vs. 22% fractional shortening), and greater evidence of diastolic dysfunction (average E wave amplitude = 568 vs. 675 mm/s) all of which were significant. Markedly greater extent of infarction was demonstrated biochemically and histologically in knockout mice compared with controls (76 vs. 29% of the left ventricle, P < 0.05) associated with striking hemorrhage and intense inflammation. Fibrosis normalized for infarct size was markedly reduced (0.006 vs. 0.022 μg hydroxyproline/mg dry weight). Thus, lack of PAI-1 in the heart exerted deleterious effects mediated, at least in part by increased inflammation and hemorrhage and attenuating of fibrosis.

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Acknowledgments

The work was supported in part by the American Diabetes Association grant No. 1-04-RA-105 entitled “Intramural Plasminogen Activator Inhibitor Type-1 (PAI-1): A Determinant of Plaque Vulnerability Associated with Type 2 Diabetes” and by a grant from the Leducq Foundation (Transatlantic Networks of Excellence for Cardiovascular Research). The technical assistance of Patricia Baumann, Keara McElroy-Yaggy, Dagnija Neimane, and Marilyn Wadsworth and the secretarial assistance of Lori Dales are deeply appreciated.

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Authors and Affiliations

  1. Cardiovascular Research Institute, University of Vermont, Colchester Research Facility, 208 South Park Drive, Colchester, VT, 05446, USA

    A. K. M. Tarikuz Zaman, David J. Schneider, Douglas J. Taatjes & Burton E. Sobel

  2. Department of Molecular and Cellular Pathobiology and Therapeutics, Nagoya City University Graduate School of Pharmaceutical Sciences, Tanabe-dori 3-1, Mizuho-ku, Nagoya, 467-8603, Japan

    Satoshi Fujii

  3. Center for Molecular and Vascular Biology, Katholieke Universiteit, Campus Gasthuisberg, O&N, Herestraat 49, 3000, Leuven, Belgium

    H. Roger Lijnen

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  1. A. K. M. Tarikuz Zaman
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  2. Satoshi Fujii
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  3. David J. Schneider
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  4. Douglas J. Taatjes
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  5. H. Roger Lijnen
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  6. Burton E. Sobel
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Correspondence to Burton E. Sobel.

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Zaman, A.K.M.T., Fujii, S., Schneider, D.J. et al. Deleterious effects of lack of cardiac PAI-1 after coronary occlusion in mice and their pathophysiologic determinants. Histochem Cell Biol 128, 135–145 (2007). https://doi.org/10.1007/s00418-007-0300-z

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