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.

Identification of Alkaloids from Corydalis yanhusuo W. T. Wang as Dopamine D1 Receptor Antagonists by Using CRE-Luciferase Reporter Gene Assay

“…GPCRs mediate various biological functions in response to a variety of ligands. GPCRs are involved in many signal transduction pathways and have been associated with numerous human diseases such as schizophrenia [ 19 ], cancers [ 20 ], and atherosclerosis [ 21 ]. Thus, these receptors have been used as therapeutic targets for a large number of drugs.…”

The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson’s Disease

“…Studies in human cells lines corroborate these findings, showing enzymatically active AADC in human promyelocytic U937 cells (Kokkinou et al, 2009), and that LPS-treatment of these cells induces TH and VMAT2 expressions (Capellino et al, 2010). Cross species examinations have further substantiated the potential generalization of dopaminergic proteins’ expression in rodent macrophages and microglia (Brown et al, 2003; Farber et al, 2005a; Flierl et al, 2007; Nakashioya et al, 2011; Yao et al, 2016). …”

“…Dopamine treatment and D1R activation has also been shown to inhibit NLRP-3 inflammasome-dependent inflammation which includes LPS-induced and neurotoxin-induced systemic inflammation (Yan et al, 2015). D1R activation has also been shown to inhibit macrophage proliferation induced by oxidized low-density lipoprotein in a MAPK and Akt-dependent manner (Yao et al, 2016). In unstimulated human monocyte-derived macrophages dopamine treatment increased IL-6 and CCL2 production (Gaskill et al, 2012).…”

Leonurine Prevents Atherosclerosis Via Promoting the Expression of ABCA1 and ABCG1 in a Pparγ/Lxrα Signaling Pathway-Dependent Manner

“…It is well received that the formation of atherosclerotic lesions, which is featured by mass deposition of macrophages-derived CE-rich foam cells within the arterial wall, is a major risk factor for atherogenesis [33, 34]. The abnormal homeostasis of cellular cholesterol is responsible for the development of AS.…”