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

Research output: Contribution to journalArticle

32 Citations (Scopus)

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)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume303
Issue number12
DOIs
StatePublished - Dec 15 2012

Fingerprint

Myocardial Ischemia
Liver
Proteins
Myocardial Infarction
Protein Binding
Hepatocytes
Up-Regulation
Cardiotonic Agents
CXC Chemokines
Bone Morphogenetic Proteins
Gene Silencing
Proteoglycans
Cardiac Myocytes
Small Interfering RNA
Glycoproteins
Ischemia
Ligands
Bone and Bones
Acids

Keywords

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

ASJC Scopus subject areas

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

Cite this

Liu, Shu Qian ; Tefft, Brandon J. ; Roberts, Derek T. ; Zhang, Li-Qun ; Ren, Yupeng ; Li, Yan Chun ; Huang, Yong ; Zhang, Di ; Phillips, Harry R. ; Wu, Yu H. / Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia. In: American Journal of Physiology - Heart and Circulatory Physiology. 2012 ; Vol. 303, No. 12.
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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.",
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Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia. / Liu, Shu Qian; Tefft, Brandon J.; Roberts, Derek T.; Zhang, Li-Qun; Ren, Yupeng; Li, Yan Chun; Huang, Yong; Zhang, Di; Phillips, Harry R.; Wu, Yu H.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 303, No. 12, 15.12.2012.

Research output: Contribution to journalArticle

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T1 - Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia

AU - Liu, Shu Qian

AU - Tefft, Brandon J.

AU - Roberts, Derek T.

AU - Zhang, Li-Qun

AU - Ren, Yupeng

AU - Li, Yan Chun

AU - Huang, Yong

AU - Zhang, Di

AU - Phillips, Harry R.

AU - Wu, Yu H.

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N2 - 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.

AB - 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.

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KW - Myocardial protection

KW - Secretory proteins

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