Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway.
Fenofibrate, a widely used hypolipidemic drug, has anti-inflammatory and anti-atherosclerotic effects in the vessel wall. In the present study, we report an anti-apoptotic property of fenofibrate in human retinal endothelial cells (HRECs) and describe an underlying molecular mechanism. Treatment with fenofibrate protected HRECs from apoptosis in response to serum deprivation in a dose-dependent manner. This inhibition of apoptosis by fenofibrate was not altered by peroxisome proliferator-activated receptor alpha (PPARalpha) antagonist MK 886, and selective agonist for PPARalpha, WY-14643 had no beneficial effects on serum deprivation-induced cell death. Fenofibrate potently induced a sustained activation of AMP-activated protein kinase (AMPK) and vascular endothelial growth factor (VEGF) mRNA expression. Furthermore, compound C, a specific AMPK inhibitor, almost completely blocked the fenofibrate-induced survival effect as well as VEGF mRNA expression. Taken together, these results suggest that fenofibrate prevents apoptotic cell death induced by serum deprivation through PPARalpha-independent, but AMPK-dependent pathway. Thus fenofibrate may have a novel therapeutic property that can control unwanted cell death found in diabetic retinopathy.
Kim
Jaetaek
J
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, 224-1 Heuk Seok-dong, Dongjak-ku, Seoul 156-755, South Korea. jtkim@cau.ac.kr
Ahn
Ji-Hyun
JH
Kim
Jeong-Hun
JH
Yu
Young-Suk
YS
Kim
Ho-Shik
HS
Ha
Joohun
J
Shinn
Soon-Hyun
SH
Oh
Yeon-Sahng
YS
D055372:AMP-Activated Protein Kinases; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000502:physiology*; D047493:PPAR alpha / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012171:Retinal Vessels / Q000166:cytology / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000960:Hypolipidemic Agents; D009097:Multienzyme Complexes; D047493:PPAR alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D011345:Fenofibrate