Nifedipine upregulates manganese superoxide dismutase expression in vascular smooth muscle cells via endothelial cell-dependent pathways.
Calcium antagonists normalize endothelial dysfunction and improve the clinical outcome in patients with hypertension. However, the mechanism underlying these beneficial effects remains to be elucidated. Here, we show that the calcium antagonist nifedipine upregulates the expression of manganese superoxide dismutase (Mn SOD), an endogenous antioxidant enzyme, in vascular smooth muscle cells (VSMC) via cellular interactions between VSMC and endothelial cells (EC). Nifedipine induced upregulation of Mn SOD activity and expression in VSMC when cocultured with EC but not when cultured individually. NG-Monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, inhibited the upregulation of Mn SOD expression induced by nifedipine. Additionally, N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino) ethanamine, a NO donor, reversed this inhibition by L-NMMA, indicating that NO may be involved in the mechanism underlying the nifedipine-induced upregulation of Mn SOD in VSMC. Preincubation of VSMC with Mn SOD antisense oligodeoxyribonucleotides (ODN) blocked the suppressive effects of nifedipine on DNA synthesis in VSMC cocultured with EC, whereas sense ODN had no effect. We conclude that the calcium antagonist nifedipine induces upregulation of Mn SOD expression in VSMC via NO derived from EC. This finding may provide some insight into the mechanism underlying the beneficial effects of calcium antagonists in patients with hypertension.
Fukuo
Keisuke
K
Department of Geriatric Medicine, Osaka University Medical School, Yamadaoka, Suita, Japan. fukuo@geriat.med.osaka-u.ac.jp
Yang
Jin
J
Suzuki
Takashi
T
Kaimoto
Taeko
T
Takemura
Yukihiro
Y
Yasuda
Osamu
O
Suhara
Toshimitsu
T
Sato
Naoyuki
N
Ogihara
Toshio
T
D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009543:Nifedipine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D014404:Tubulin / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D014404:Tubulin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D009543:Nifedipine