The calcium channel blocker cilnidipine selectively suppresses hypoxia-inducible factor 1 activity in vascular cells.
Calcium ion is one of the most important second messengers of cellular signal transduction including hypoxia-elicited signals. In this study, we investigated the effects of the L-type calcium channel blockers such as nifedipine, efonidipine cilnidipine, diltiazem, and verapamil, on the activity of hypoxia-inducible factor-1 (HIF-1), a key transcription factor in control of hypoxia-induced gene expression. Using the lung carcinoma cell line A549 cells, human aortic smooth muscle cells, and human umbilical vein endothelial cells, we demonstrated that cilnidipine exclusively suppressed HIF-1 activity and the expressions of downstream genes in a cell-type specific manner. We also demonstrated that cilnidipine blocked the synthesis of the HIF-1alpha protein not by affecting activity of the intracellular hypoxia-sensing element prolyl hydroxylases but inhibiting activity of Akt and mitogen-activated protein kinase and that the inhibition is not dependent on the effect on calcium homeostasis.
Department of Anesthesia, Kyoto University Hospital, Kyoto, Japan.
Seiko
S
Oda
Tomoyuki
T
Oda
Satoshi
S
Takabuchi
Kenichiro
K
Nishi
Takuhiko
T
Wakamatsu
Tomoharu
T
Tanaka
Takehiko
T
Adachi
Kazuhiko
K
Fukuda
Ryuji
R
Nohara
Kiichi
K
Hirota
D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004095:Dihydropyridines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D051793:Hypoxia-Inducible Factor 1; C065927:cilnidipine; D010100:Oxygen; D002118:Calcium