Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia.
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.
Biomedical Engineering Department, Northwestern University, Evanston, Illinois 60208-3107, USA. sliu@northwestern.edu
Shu Q
SQ
Liu
Brandon J
BJ
Tefft
Derek T
DT
Roberts
Li-Qun
LQ
Zhang
Yupeng
Y
Ren
Yan Chun
YC
Li
Yong
Y
Huang
Di
D
Zhang
Harry R
HR
Phillips
Yu H
YH
Wu
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D023921:Coronary Stenosis / Q000150:complications; D004195:Disease Models, Animal; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009077:Mucins / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D020880:Neuregulins / Q000378:metabolism; D009961:Orosomucoid / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013997:Time Factors; D000071165:Trefoil Factor-3; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D002352:Carrier Proteins; D009077:Mucins; D020880:Neuregulins; D009961:Orosomucoid; D034741:RNA, Small Interfering; C493263:Tff3 protein, mouse; D000071165:Trefoil Factor-3; C579574:alpha-1-acid glycoprotein 2, mouse; C517553:crossveinless 2 protein, mouse; C414620:fibroblast growth factor 21; C467747:neuregulin-4; D005346:Fibroblast Growth Factors