Dopamine D1-Like Receptors Suppress the Proliferation of Macrophages Induced by Ox-LDL

Abstract

Background/Aims: Oxidized low-density lipoprotein (Ox-LDL) induces macrophage proliferation, a key physiological process which leads to atherosclerosis. The aim of this study was to determine the effects of dopamine D1-like receptors on macrophage proliferation induced by Ox-LDL. Methods: The expression of dopamine D1-like receptors was determined by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting. The effect of D1-like receptors on macrophage proliferation induced by Ox-LDL was measured by 3[H]-thymidine incorporation and cell number count. Results: Dopamine D1-like receptors were present in macrophages as determined by immunohistochemistry, RT-PCR and immunoblotting. A D1-like receptor agonist, fenoldopam, which by itself had no effect on macrophage proliferation, inhibited the stimulatory effect of Ox-LDL on macrophage proliferation. This was further confirmed by the D1-like receptor antagonist SCH 23390 blocking the effect of fenoldopam, thereby indicating that the fenoldopam action was receptor specific. Phosphatidylinositol 3-kinase (PI3K/Akt) and mitogen-activated protein kinase (MAPK/ERK) pathways were also involved in the proliferative effect of Ox-LDL because in the presence of PI3K/Akt or MAPK/ERK inhibitors, LY294002 or PD98059, the stimulatory effects of Ox-LDL were blocked. Moreover, the stimulatory effect of Ox-LDL on the phosphorylation of ERK and Akt was significantly reduced by fenoldopam in macrophages. Additional experiments found that both D1 and D5 receptor expression was lower in the peritoneal macrophages from Apolipoprotein E-deficient mice compared to the control C57Bl/6J mice. Conclusions: Macrophages express D1-like receptors. The activation of the D1-like receptors significantly inhibits Ox-LDL-induced macrophage proliferation, possibly through the inhibition of the PI3K/Akt and MAPK/ERK signaling pathways.