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.