Cardiac ischemia-reperfusion injury induces matrix metalloproteinase-2 expression through the AP-1 components FosB

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Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
07:23

Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury

Published on: March 7, 2022

Maria Alejandra Alfonso-Jaume1, Marina R Bergman, Rajeev Mahimkar

  • 1Dept. of Medicine, 111J, San Francisco Veterans Affairs Medical Center/Univ. of California San Francisco, 4150 Clement St., San Francisco, CA 94121, USA.

American Journal of Physiology. Heart and Circulatory Physiology
|May 16, 2006
PubMed

Insights

Ischemia-reperfusion injury in the heart activates matrix metalloproteinase-2 (MMP-2) transcription. This process involves oxidant stress-induced activator protein-1 (AP-1) transcription factors, leading to increased MMP-2 generation in cardiac cells.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cellular Signaling

Background:

  • Matrix metalloproteinase-2 (MMP-2) plays a critical role in cardiac response to injury, influencing ventricular function and post-infarction remodeling.
  • Elevated MMP-2 during ischemia-reperfusion (I/R) suggests de novo synthesis, but its transcriptional regulation remains unelucidated.

Purpose of the Study:

  • To investigate the transcriptional regulation and cellular origins of MMP-2 during acute global I/R injury in the heart.
  • To identify the molecular mechanisms driving MMP-2 gene expression following I/R.

Main Methods:

  • Utilized transgenic mice with an MMP-2 promoter-beta-galactosidase reporter system to assess promoter activity.
  • Employed real-time PCR and Western blot to confirm MMP-2 transcription and translation.
  • Investigated the role of activator protein-1 (AP-1) components using nuclear extracts, immunohistochemistry, and chromatin immunoprecipitation (ChIP).

Main Results:

  • I/R injury rapidly activated the MMP-2 promoter, with beta-galactosidase expression observed in cardiomyocytes, fibroblasts, and endothelial cells.
  • MMP-2 transcription and translation were confirmed and found to be inhibited by a hydroxyl radical scavenger.
  • I/R injury increased nuclear abundance and binding of AP-1 components JunB and FosB to the MMP-2 promoter, shifting from JunB homodimers to JunB/FosB heterodimers.

Conclusions:

  • Enhanced MMP-2 transcription and translation following cardiac I/R injury are mediated by oxidant stress-induced activation of specific AP-1 transcription factors.
  • These findings elucidate a key molecular pathway regulating MMP-2 expression in response to ischemic heart injury.

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