HSP70-1 is required for interleukin-5-induced angiogenic responses through eNOS pathway.
We report a pivotal role for IL-5 as an angiogenic activator. IL-5 increased proliferation, migration and colony tube formation in HUVECs associated with the phosphorylation of ERK and AKT/eNOS, and promoted microvessel sprouting from an angiogenesis animal model. The angiogenic effects were confirmed in IL-5-deficient mice and addition of IL-5 antibody. HSP70-1 was identified via expression profiling following IL-5 stimulation. A siRNA knockdown of HSP70-1 suppressed angiogenic responses and eNOS phosphorylation induced by IL-5. HSP70-1 overexpression enhanced IL-5-induced angiogenic responses. In addition, IL-5-induced neo-vascular formation was verified in both HSP70-1 knockout and HSP70-1 transgenic mice. Furthermore, transcription factor AP-1 was a main factor in IL-5-induced HSP70-1 in response to ERK and AKT signaling pathway. Angiogenic responses induced by VEGF had no effect in either HSP70-1 siRNA in vitro or HSP70-1 knockout mice. IL-5-induced angiogenic responses depended on the binding of IL-5Rα. Our data demonstrate that binding of IL-5 to IL-5Rα receptors enhances angiogenic responses by stimulating the expression of HSP70-1 via the eNOS signaling pathway.
Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Korea.
Sung Lyea
SL
Park
School of Korean Medicine and Healthy Aging Korean Medicine Research Center, Pusan National University, Yangsan, 626-780, Republic of Korea.
Tae-Wook
TW
Chung
Biomedical Research Institute, Bundang Hospital, Seoul National University, 647-707, Korea.
Sangtae
S
Kim
Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Korea.
Byungdoo
B
Hwang
NAR Center, Inc., Daejeon Oriental Hospital of Daejeon University, Daejeon 301-724, Republic of Korea.
Jung Min
JM
Kim
Department of Cosmetic Science, Hoseo University, Asan-si 31499, Republic of Korea.
Hwan Myung
HM
Lee
Department of Parasitology and Genetics, Kosin University College of Medicine, Busan 602-702, Republic of Korea.
Hee-Jae
HJ
Cha
EBO Co., Ltd., Future Convergence Technology Center, Cheongwon-Gun, Chungbuk, Korea.
Yoonhee
Y
Seo
EBO Co., Ltd., Future Convergence Technology Center, Cheongwon-Gun, Chungbuk, Korea.|Department of Biology, Chungbuk National University, Cheongju, Chungbuk, Korea.
Soo Young
SY
Choe
School of Korean Medicine and Healthy Aging Korean Medicine Research Center, Pusan National University, Yangsan, 626-780, Republic of Korea.
Ki-Tae
KT
Ha
Department of Veterinary Surgery, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea.
Gonhyung
G
Kim
Personalized Tumor Engineering Research Center, Department of Urology, Chungbuk National University, Cheongju, Chungbuk 361-763, South Korea.
Seok-Joong
SJ
Yun
Department of Food Science and Nutrition, Jeju National University, Jeju, Jeju Special Self-Governing Province, 690-756, South Korea.
Sung-Soo
SS
Park
Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 614-052, South Korea.
Yung Hyun
YH
Choi
Department of Physiology, College of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
Bo Kyung
BK
Kim
Personalized Tumor Engineering Research Center, Department of Urology, Chungbuk National University, Cheongju, Chungbuk 361-763, South Korea.
Won-Tae
WT
Kim
Department of Biomedical Engineering, Chungbuk National University, Cheongju 361-763, Korea.
Eun-Jong
EJ
Cha
NewYork-Presbyterian Hospital, New York, NY 10065, USA.
Cam
C
Patterson
Personalized Tumor Engineering Research Center, Department of Urology, Chungbuk National University, Cheongju, Chungbuk 361-763, South Korea.
Wun-Jae
WJ
Kim
Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Korea.
Sung-Kwon
SK
Moon
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015848:Interleukin-5 / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000187:drug effects / Q000254:growth & development; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
D018840:HSP70 Heat-Shock Proteins; D015848:Interleukin-5; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C081884:heat-shock protein 70.1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases