Hypoxia-inducible factor 1alpha is deregulated by the serum of rats with adjuvant-induced arthritis.
Rheumatoid arthritis (RA) is known to be associated with increased risks of hypoxia-related diseases, whose progresses are critically determined by HIF-1alpha. The authors hypothesized that the hypoxia-related complications of RA are associated with HIF-1alpha deregulation by some factor(s) in RA serum. Arthritis was induced in female Lewis rats by injecting complete Freund's adjuvant. The effects of arthritic rat serum (ARS) on hypoxic responses were investigated by incubating Hep3B cells in ARS. In the presence of ARS, HIF-1alpha was down-regulated and inactivated under hypoxic conditions. ARS inactivated AKT and mTOR, which led to impaired HIF-1alpha protein synthesis. Furthermore, insulin was found to be deficient in ARS and insulin supplementation fully recovered HIF-1alpha synthesis with AKT and mTOR activation. These results suggest that HIF-1alpha deregulation by components in serum is responsible for the RA-associated aggravation of hypoxic diseases in extra-articular tissues.
Kim
Hye-Lim
HL
Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea.
Cho
Young-Suk
YS
Choi
Hong
H
Chun
Yang-Sook
YS
Lee
Zang Hee
ZH
Park
Jong-Wan
JW
D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood* / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D044967:Serum / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011494:Protein Kinases; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases