Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia. Am J Physiol Heart Circ Physiol 2012 Dec 15;303(12):H1446-58
Date
10/16/2012Pubmed ID
23064833DOI
10.1152/ajpheart.00362.2012Scopus ID
2-s2.0-84871258821 (requires institutional sign-in at Scopus site) 55 CitationsAbstract
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.
Author List
Liu SQ, Tefft BJ, Roberts DT, Zhang LQ, Ren Y, Li YC, Huang Y, Zhang D, Phillips HR, Wu YHAuthor
Brandon J. Tefft PhD Assistant Professor in the Biomedical Engineering department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCarrier Proteins
Coronary Stenosis
Disease Models, Animal
Female
Fibroblast Growth Factors
Hepatocytes
Liver
Male
Mice
Mice, Inbred C57BL
Mucins
Myocardial Ischemia
Neuregulins
Orosomucoid
RNA, Small Interfering
Time Factors
Trefoil Factor-3
Up-Regulation