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Extracellular Nucleotides Can Induce Chemokine (C-C motif) Ligand 2 Expression in Human Vascular Smooth Muscle Cells.

ABSTRACT: To understand the roles of purinergic receptors and cellular molecules below the receptors in the vascular inflammatory response, we determined if extracellular nucleotides up-regulated chemokine expression in vascular smooth muscle cells (VSMCs). Human aortic smooth muscle cells (AoSMCs) abundantly express P2Y(1), P2Y(6), and P2Y(11) receptors, which all respond to extracellular nucleotides. Exposure of human AoSMCs to NAD(+), an agonist of the human P2Y(11) receptor, and NADP(+) as well as ATP, an agonist for P2Y(1) and P2Y(11) receptors, caused increase in chemokine (C-C motif) ligand 2 gene (CCL2) transcript and CCL2 release; however, UPT did not affect CCL2 expression. CCL2 release by NAD(+) and NADP(+) was inhibited by a concentration dependent manner by suramin, an antagonist of P2-purinergic receptors. NAD(+) and NADP(+) activated protein kinase C and enhanced phosphorylation of mitogen-activated protein kinases and Akt. NAD(+)- and NADP(+)-mediated CCL2 release was significantly attenuated by SP6001250, U0126, LY294002, Akt inhibitor IV, RO318220, GF109203X, and diphenyleneiodium chloride. These results indicate that extracellular nucleotides can promote the proinflammatory VSMC phenotype by up-regulating CCL2 expression, and that multiple cellular elements, including phosphatidylinositol 3-kinase, Akt, protein kinase C, and mitogen-activated protein kinases, are involved in that process.

SUBMITTER: Kim JI

PROVIDER: S-EPMC3062081 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Extracellular Nucleotides Can Induce Chemokine (C-C motif) Ligand 2 Expression in Human Vascular Smooth Muscle Cells.

Kim Jeung-Il JI Kim Hye-Young HY Kim Sun-Mi SM Lee Sae-A SA Son Yong-Hae YH Eo Seong-Kug SK Rhim Byung-Yong BY Kim Koanhoi K

The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 20110228 1

To understand the roles of purinergic receptors and cellular molecules below the receptors in the vascular inflammatory response, we determined if extracellular nucleotides up-regulated chemokine expression in vascular smooth muscle cells (VSMCs). Human aortic smooth muscle cells (AoSMCs) abundantly express P2Y(1), P2Y(6), and P2Y(11) receptors, which all respond to extracellular nucleotides. Exposure of human AoSMCs to NAD(+), an agonist of the human P2Y(11) receptor, and NADP(+) as well as ATP ...[more]

PMID: 21461238

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Project description:BACKGROUND:Recently, we provided evidence that ?1-adrenergic receptors (ARs) in vascular smooth muscle are regulated by chemokine (C-X-C motif) receptor (CXCR) 4 and atypical chemokine receptor 3 (ACKR3). While we showed that CXCR4 controls ?1-ARs through formation of heteromeric receptor complexes in human vascular smooth muscle cells (hVSMCs), the molecular basis underlying cross-talk between ACKR3 and ?1-ARs is unknown. METHODS AND RESULTS:We show that ACKR3 agonists inhibit inositol trisphosphate production in hVSMCs on stimulation with phenylephrine. In proximity ligation assays and co-immunoprecipitation experiments, we observed that recombinant and endogenous ACKR3 form heteromeric complexes with ?1A/B/D-AR. While small interfering RNA knockdown of ACKR3 in hVSMCs reduced ?1B/D-AR:ACKR3, CXCR4:ACKR3, and ?1B/D-AR:CXCR4 complexes, small interfering RNA knockdown of CXCR4 reduced ?1B/D-AR:ACKR3 heteromers. Phenylephrine-induced inositol trisphosphate production from hVSMCs was abolished after ACKR3 and CXCR4 small interfering RNA knockdown. Peptide analogs of transmembrane domains 2/4/7 of ACKR3 showed differential effects on heteromerization between ACKR3, ?1A/B/D-AR, and CXCR4. While the transmembrane domain 2 peptide interfered with ?1B/D-AR:ACKR3 and CXCR4:ACKR3 heteromerization, it increased heteromerization between CXCR4 and ?1A/B-AR. The transmembrane domain 2 peptide inhibited ACKR3 but did not affect ?1b-AR in ?-arrestin recruitment assays. Furthermore, the transmembrane domain 2 peptide inhibited phenylephrine-induced inositol trisphosphate production in hVSMCs and attenuated phenylephrine-induced constriction of mesenteric arteries. CONCLUSIONS:?1-ARs form hetero-oligomeric complexes with the ACKR3:CXCR4 heteromer, which is required for ?1B/D-AR function, and activation of ACKR3 negatively regulates ?1-ARs. G protein-coupled receptor hetero-oligomerization is a dynamic process, which depends on the relative abundance of available receptor partners. Endogenous ?1-ARs function within a network of hetero-oligomeric receptor complexes.

Dataset Information

Extracellular Nucleotides Can Induce Chemokine (C-C motif) Ligand 2 Expression in Human Vascular Smooth Muscle Cells.

Publications

Extracellular Nucleotides Can Induce Chemokine (C-C motif) Ligand 2 Expression in Human Vascular Smooth Muscle Cells.

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