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Amlodipine inhibits cell proliferation via PKD1-related pathway

Takayoshi Ohba1, Hiroyuki Watanabe, Manabu Murakami

  • 1Department of Pharmacology, Akita University School of Medicine, 1-1-1, Hondoh, Akita 010-8543, Japan.

Biochemical and Biophysical Research Communications
|February 27, 2008
PubMed

Insights

Amlodipine reduces human coronary artery smooth muscle cell proliferation by increasing p21((Waf1/Cip1)) expression. This effect involves Polycystic Kidney Disease 1 (PKD1) signaling through the JAK/STAT pathway.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cell Biology
  • Pharmacology

Background:

  • Human coronary artery smooth muscle cell (hCASMC) proliferation contributes to coronary artery disease progression.
  • Amlodipine, an antihypertensive, inhibits hCASMC proliferation by upregulating p21((Waf1/Cip1)).
  • Polycystic Kidney Disease 1 (PKD1) is implicated in cell cycle inhibition via p21((Waf1/Cip1)).

Purpose of the Study:

  • To elucidate the role of PKD1-related signaling in amlodipine's antiproliferative effects on hCASMCs.
  • To investigate the mechanism by which amlodipine affects hCASMCs, focusing on PKD1 and JAK/STAT signaling.

Main Methods:

  • Cultured hCASMCs expressing PKD1 were stimulated with serum.
  • Amlodipine treatment, PKD1 overexpression, and dominant-negative PKD1 were used.
  • Western blotting for phosphorylated JAK2 and luciferase assays for STAT1 enhancer activity were performed.

Main Results:

  • Amlodipine dose- and time-dependently increased p21((Waf1/Cip1)) expression, reducing hCASMC proliferation.
  • PKD1 overexpression mimicked amlodipine's inhibitory effect, while dominant-negative PKD1 reversed it.
  • Amlodipine and PKD1 overexpression increased phosphorylated JAK2, and PKD1 overexpression enhanced STAT1 activity.

Conclusions:

  • PKD1 is involved in the antiproliferative action of amlodipine on hCASMCs.
  • The mechanism involves the upregulation of p21((Waf1/Cip1)) through the JAK/STAT signaling pathway mediated by PKD1.

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