Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue.
Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia. Such processes are present in not only the heart, but also remote organs. In this investigation, we demonstrated a cardioprotective process involving FGF21 from the liver and adipose tissue. In response to myocardial ischemia/reperfusion injury in the mouse, FGF21 was upregulated and released from the hepatic cells and adipocytes into the circulation and interacted with FGFR1 in cardiomyocytes under the mediation of the cell membrane protein β-Klotho, inducing FGFR1 phosphorylation. This action caused phosphorylation of the signaling molecules PI3K p85, Akt1, and BAD, thereby reducing caspase 3 activity, cell death, and myocardial infarction in association with improvement of myocardial function. These observations suggest that FGF21 is upregulated and released from the liver and adipose tissue in myocardial injury, contributing to myocardial protection by the mediation of the FGFR1/β-Klotho-PI3K-Akt1-BAD signaling network.
Biomedical Engineering Department, Northwestern University, Evanston, IL 60208, USA.
Shu Q
SQ
Liu
Derek
D
Roberts
Alexei
A
Kharitonenkov
Brian
B
Zhang
Samuel M
SM
Hanson
Yan Chun
YC
Li
Li-Qun
LQ
Zhang
Yu H
YH
Wu
D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004703:Endocrine System / Q000378:metabolism* / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D020868:Gene Silencing; D005966:Glucuronidase; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics; D000090265:Klotho Proteins; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D017202:Myocardial Ischemia / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D051025:bcl-Associated Death Protein / Q000378:metabolism
D002316:Cardiotonic Agents; D053148:Caspase 3; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D000090265:Klotho Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051025:bcl-Associated Death Protein; C414620:fibroblast growth factor 21