Objectives-High-density lipoprotein (HDL) levels are inversely proportional to the risk of atherosclerosis, but mechanisms of HDL atheroprotection remain unclear. Monocyte chemoatractant protein-1 (MCP-1) constitutes an early component of inflammatory response in atherosclerosis. Here we investigated the influence of HDL on MCP-1 production in vascular smooth muscle cells (VSMCs) and rat aortic explants. Methods and Results-HDL inhibited the thrombin-induced production of MCP-1 in a concentration-dependent manner.The HDL-dependent inhibition of MCP-1 production was accompanied by the suppression of reactive oxygen species (ROS), which regulate the MCP-1 production in VSMCs. HDL inhibited NAD(P)H oxidase, the preponderant source of ROS in the vasculature, and prevented the activation of Rac1, which precedes NAD(P)H-oxidase activation. The HDL capacity to inhibit MCP-1 production, ROS generation, and NAD(P)H-oxidase activation was emulated by sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), two lysosphingolipids present in HDL, but not by apolipoprotein A-I. HDL-, S1P-, and SPC-induced inhibition of MCP-1 production was attenuated in VSMCs pretreated with VPC23019, an antagonist of lysosphingolipid receptors S1P 1 and S1P 3 , but not by JTE013, an antagonist of S1P 2 . In addition, HDL, S1P, and SPC failed to inhibit MCP1 production and ROS generation in aortas from S1P 3 -and SR-B1-deficient mice. Conclusion-HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent ROS generation and MCP-1 production in a process that requires coordinate signaling through S1P 3 and SR-B1 receptors. (Arterioscler Thromb Vasc Biol. 2008;28:1542-1548)Key Words: HDL Ⅲ sphingosine-1-phosphate Ⅲ MCP-1 Ⅲ ROS Ⅲ NADPH-oxidase M onocyte infiltration into the vessel wall is an initial step in the formation of atherosclerotic lesion. 1,2 Monocyte chemoattractant protein-1 (MCP-1) is a key regulator of monocyte recruitment to sites of vascular inflammation. [2][3][4] In addition, MCP-1 induces several proinflammatory changes including secretion of cytokines and expression of adhesion molecules. 2-4 MCP-1 was detected in atherosclerotic lesion, and elevated levels of MCP-1 were encountered in acute coronary syndromes. 2-4 Animals genetically modified to lack MCP-1 or its receptor, CCR2, displayed reduced atherosclerotic lesions, whereas overexpression of MCP-1 in macrophages led to increased susceptibility to atherosclerosis. [2][3][4] Numerous studies documented an inverse relationship between high-density lipoprotein (HDL) levels and the progression of atherosclerosis and suggested that antiatherogenic effects of HDL are related to inflammation and its sequel. 5 For instance, HDL inhibits expression of adhesion molecules and reduces leukocyte homing to arterial endothelium. 5,6 Suppression of cytokine and chemokine production by HDL was observed after infusion of reconstituted HDL in animal models of inflammation. 7 The inverse relationship between HDL and acute phase proteins was repeatedly reported. 8 De...

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BackgroundThe currently approved therapies fail in a substantial number of colorectal cancer (CRC) patients due to the molecular heterogeneity of CRC, hence new efficient drug combinations are urgently needed. Emerging data indicate that 5-azanucleosides are able to sensitize cancer cells to the standard chemotherapeutic agents and contribute to overcoming intrinsic or acquired chemoresistance.MethodsCRC cells with different genetic backgrounds (HCT116, DLD-1, HT-29) were sequentially treated with 5-azanucleosides and topoisomerase inhibitors. The combined effects of these two drug classes on cell viability, apoptosis, signaling pathways, and colony formation were investigated.ResultsHere, we demonstrate that pretreatment with DNA demethylating agents, 5-aza-2′-deoxycytidine and 5-azacytidine, sensitizes CRC cells to topoisomerase inhibitors (irinotecan, etoposide, doxorubicin, mitoxantrone), reducing cell viability and clonogenicity and increasing programmed cell death more effectively than individual compounds at the same or even higher concentrations. 5-Azanucleosides did not cause considerable immediate toxic effects as evaluated by analysis of cell viability, apoptosis, DNA damage (γH2A.X), and endoplasmic reticulum (ER) stress (CHOP). However, 5-azanucleosides exerted long-lasting effects, reducing cell viability, changing cell morphology, and affecting phosphoinositide 3-kinase (PI3-kinase)/Akt signaling pathway. We found that a single exposure to 5-azanucleosides is sufficient to induce long-lasting sensitization to topoisomerase inhibitors. The combinatorial, but not separate, treatment with low doses of 5-aza-2′-deoxycytidine (0.1 μM) and etoposide (0.5 μM) caused a long-lasting (almost 70 days) reduction in clonogenic/replating ability of DLD-1 cells.ConclusionsThese results suggest that sequential treatments with DNA demethylating agents and topoisomerase inhibitors may exert clinically relevant anticancer effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2925-6) contains supplementary material, which is available to authorized users.

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