Hypoxic regulation of VEGF, HIF-1(alpha) in coronary collaterals development.
BACKGROUND
The interindividual variability for the development of collaterals in coronary artery disease is dependent on the hypoxic induction level of VEGF. To determine whether the hypoxic induction of VEGF is controlled by the transcription of HIF-1 (alpha), the VEGF and HIF-1 (alpha) m-RNA levels were correlated to hypoxia in monocytes harvested from patients with coronary artery disease.


METHODS
The collateral scoring system used was modified from the TIMI system. The mononuclear cell layer of the patients' blood was cultured in hypoxia (1% O2, 5% CO2, 94%N2) and normoxia (5% CO2, 95% room air) for 17 hours. The VEGF and HIF-1 (alpha) mRNA levels were measured using a RT-PCR technique. We calculated the fold inductionsof VEGF, HIF-1 (alpha) mRNA with hypoxia by dividing the hypoxic and the normoxic values.


RESULTS
We found significantly higher hypoxic inductions of VEGF m-RNA in patients with collaterals compared to patients with no collaterals. However, there was no differencein the hypoxic inductions of HIF-1 (alpha) between the two groups (VEGF m-RNA mean fold inductions 3.71 +/- 3.30 versus 1.65 +/- 0.62, p=0.012, HIF-1(alpha) mRNA 1.42 +/- 0.58 versus 1.20 +/- 0.39, p=0.165).


CONCLUSIONS
We concluded that the interindividual variability in the hypoxic inductions of VEGF m-RNA in monocytes in patients is not controlled by the transcriptional levels of HIF-1 (alpha) with hypoxia. These findings suggest that a mechanism such as the post-transcriptional modification of HIF-1(alpha) is involved in the hypoxic inductions of VEGF.
Department of Internal Medicine, Kangbuk Samsung Hospital Sungkyunkwan University School of Medicine, Seoul, Korea.
Ki Chul
KC
Sung
Kyung Soo
KS
Kim
Sang
S
Lee
D002478:Cells, Cultured; D003097:Collateral Circulation; D003324:Coronary Artery Disease / Q000378:metabolism; D003326:Coronary Circulation; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A