Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia

Shu Qian Liu, Brandon J. Tefft, Derek T. Roberts, Li-Qun Zhang, Yupeng Ren, Yan Chun Li, Yong Huang, Di Zhang, Harry R. Phillips, Yu H. Wu

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Abstract

Myocardial ischemia (MI) activates innate cardioprotective mechanisms, enhancing cardiomyocyte tolerance to ischemia. Here, we report a MI-activated liver-dependent mechanism for myocardial protection. In response to MI in the mouse, hepatocytes exhibited 6- to 19-fold upregulation of genes encoding secretory proteins, including α-1-acid glycoprotein (AGP)2, bone morphogenetic protein-binding endothelial regulator (BMPER), chemokine (C-X-C motif) ligand 13, fibroblast growth factor (FGF)21, neuregulin (NRG)4, proteoglycan 4, and trefoil factor (TFF)3. Five of these proteins, including AGP2, BMPER, FGF21, NRG4, and TFF3, were identified as cardioprotective proteins since administration of each protein significantly reduced the fraction of myocardial infarcts (37 ± 9%, 34 ± 7%, 32 ± 8%, 39 ± 6%, and 31 ± 7%, respectively, vs. 48 ± 7% for PBS at 24 h post-MI). The serum level of the five proteins elevated significantly in association with protein upregulation in hepatocytes post-MI. Suppression of a cardioprotective protein by small interfering (si)RNA-mediated gene silencing resulted in a significant increase in the fraction of myocardial infarcts, and suppression of all five cardioprotective proteins with siRNAs further intensified myocardial infarction. While administration of a single cardioprotective protein mitigated myocardial infarction, administration of all five proteins furthered the beneficial effect, reducing myocardial infarct fractions from PBS control values from 46 ± 6% (5 days), 41 ± 5% (10 days), and 34 ± 4% (30 days) to 35 ± 5%, 28 ± 5%, and 24 ± 4%, respectively. These observations suggest that the liver contributes to cardioprotection in MI by upregulating and releasing protective secretory proteins. These proteins may be used for the development of cardioprotective agents.

Original languageEnglish (US)
Pages (from-to)H1446-H1458
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume303
Issue number12
DOIs
StatePublished - Dec 15 2012

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Keywords

  • Cardiohepatic interaction
  • Hepatocytes
  • Myocardial infarction
  • Myocardial protection
  • Secretory proteins

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Liu, S. Q., Tefft, B. J., Roberts, D. T., Zhang, L-Q., Ren, Y., Li, Y. C., Huang, Y., Zhang, D., Phillips, H. R., & Wu, Y. H. (2012). Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia. American Journal of Physiology - Heart and Circulatory Physiology, 303(12), H1446-H1458. https://doi.org/10.1152/ajpheart.00362.2012