Amlodipine inhibits cell proliferation via PKD1-related pathway.
Human coronary artery smooth muscle cell (hCASMC) proliferation is involved in the progression of coronary artery disease. Amlodipine, a widely used antihypertensive drug, exerts antiproliferative effects by increasing the expression of p21((Waf1/Cip1)). Polycystic kidney disease 1 (PKD1) is also involved in cell cycle inhibition via p21((Waf1/Cip1)) up-regulation. We clarified the involvement of PKD1-related signaling on hCASMCs. Cultured hCASMCs, which constitutively express PKD1, were stimulated with 5% serum. Amlodipine increased p21((Waf1/Cip1)) expression in a dose- and time-dependent manner, resulting in reduced hCASMC proliferation. The inhibitory effect of amlodipine was mimicked by overexpression of PKD1 and was reversed by a dominant-negative version of PKD1 (R4227X). Immunoblot analysis showed that phosphorylated JAK2 was increased by amlodipine treatment or PKD1 overexpression. A luciferase assay revealed that the overexpression of PKD1 induced STAT1 enhancer activity. These data suggest that PKD1 contributes to the antiproliferative effect of amlodipine on hCASMCs via JAK/STAT signaling and p21((Waf1/Cip1)) up-regulation.
Ohba
Takayoshi
T
Department of Pharmacology, Akita University School of Medicine, 1-1-1, Hondoh, Akita 010-8543, Japan.
Watanabe
Hiroyuki
H
Murakami
Manabu
M
Radovanovic
Milena
M
Iino
Kenji
K
Ishida
Masaru
M
Tosa
Shinya
S
Ono
Kyoichi
K
Ito
Hiroshi
H
D017311:Amlodipine / Q000008:administration & dosage*; D000959:Antihypertensive Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050396:TRPP Cation Channels / Q000378:metabolism*
D017311:Amlodipine; D000959:Antihypertensive Agents; D050396:TRPP Cation Channels