Increased Expression of Plasminogen Activator Inhibitor-1 in Cardiomyocytes Contributes to Cardiac Fibrosis after Myocardial Infarction

Kyosuke Takeshita, Mutsuharu Hayashi, Shigeo Iino, Takahisa Kondo, Yasuya Inden, Mitsunori Iwase, Tetsuhito Kojima, Makoto Hirai, Masafumi Ito, David J. Loskutoff, Hidehiko Saito, Toyoaki Murohara, Koji Yamamoto

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102 Citations (Scopus)


Plasminogen activator inhibitor-1 (PAI-1) plays a critical role in tissue fibrosis by inactivating matrix metalloproteinases, which might effect on the progression of left ventricular dysfunction. However, little has been known about the expression of PAI-1 during cardiac remodeling. We used a mouse model of myocardial infarction (MI) by coronary ligation, in which the progression of left ventricular remodeling was confirmed by echocardiography. Histological examination showed that interstitial and perivascular fibrosis progressed in the post-MI (PMI) heart at 4 weeks after the procedure. We observed the dramatic induction of cardiac PAI-1 mRNA and PAI-1 antigen in plasma in the PMI mice, as compared with the sham-operated (sham) mice. In situ hybridization analysis demonstrated that strong signals for PAI-1 mRNA were localized to cardiomyocytes in the boarder of infarct area and around fibrous lesions, and to perivascular mononuclear cells, which seemed to be mast cells, only in hearts of the PMI mice. Importantly, less development of cardiac fibrosis after MI was observed in mice deficient in PAI-1 as compared to wild-type mice. The mRNA expression of cytokines, transforming growth factor-β, and tumor necrosis factor-α was also increased in hearts of the PMI mice, but not in the sham mice. These observations suggest that cardiomyocytes and mast cells contribute to the increased PAI-1 expression, resulting in the development of interstitial and perivascular fibrosis in the PMI heart, and that the regional induction of cytokines may be involved in this process.

Original languageEnglish
Pages (from-to)449-456
Number of pages8
JournalAmerican Journal of Pathology
Issue number2
Publication statusPublished - 02-2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine


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