Up-regulation of endothelial monocyte chemoattractant protein-1 by coplanar PCB77 is caveolin-1-dependent

Abstract

Atherosclerosis, the primary cause of heart disease and stroke is initiated in the vascular endothelium, and risk factors for its development include environmental exposure to persistent organic pollutants. Caveolae are membrane microdomains involved in regulation of many signaling pathways, and in particular in endothelial cells. We tested the hypothesis that intact caveolae are required for coplanar PCB77-induced up-regulation of monocyte chemoattractant protein-1 (MCP-1), an endotheliumderived chemokine that attracts monocytes into sub-endothelial space in early stages of the atherosclerosis development. Atherosclerosis-prone LDL-R −/− mice (control) or caveolin-1 −/− /-LDL-R −/− mice were treated with PCB77. PCB77 induced aortic mRNA expression and plasma protein levels of MCP-1 in control, but not caveolin-1 −/− /LDL-R −/− mice. To study the mechanism of this effect, primary endothelial cells were used. PCB77 increased MCP-1 levels in endothelial cells in a time-and concentration-dependent manner. This effect was abolished by caveolin-1 silencing using siRNA. Also, MCP-1 up-regulation by PCB77 was prevented by inhibiting p38 and c-Jun N-terminal kinase (JNK), but not ERK1/2, suggesting regulatory functions via p38 and JNK MAPK pathways. Finally, pretreatment of endothelial cells with the aryl hydrocarbon receptor (AhR) inhibitor α-naphthoflavone (α-NF) partially blocked MCP-1 up-regulation. Thus, our data demonstrate that coplanar PCB77 can induce MCP-1 expression by endothelial cells and that this effect is mediated by AhR, as well as p 38 and JNK MAPK pathways. Intact caveolae are required for these processes both in vivo and in vitro. This further supports a key role for caveolae in vascular inflammation induced by persistent organic pollutants.

Inflammatory response and insulin signaling alteration induced by PCB77

“…1b). Up-regulation of endothelial MCP-1 by PCB77 has been recently verified by Majkova et al (2009), who considered that the increase of MCP-1 by PCB77 is caveolin-1-dependent. But the adhesion assay has not yet been detected.…”

Comparative gene responses to collected ambient particles in vitro: endothelial responses

“…Our data suggest a similar synergistic effect on CCL-2 secretion in APM-treated endothelial cells. This could have important implications for systemic disease associated with APM exposure as CCL-2 plays a key role in the vascular and renal consequences of the metabolic syndrome (15,36,54). Finally, CEBPD has been reported to enhance CCL-2 transcription separate from NF-B activity in vascular smooth muscle cells (60).…”

Exercise protects against PCB-induced inflammation and associated cardiovascular risk factors

“…Importantly, when in the presence of PCB 77, CYP1A1 can become uncoupled and increase the levels of cellular reactive oxygen species (ROS), leading to induction of pro-inflammatory genes and subsequent vascular dysfunction (Kopf & Walker, 2010). Our laboratory has demonstrated previously that exposure to PCB 77 increases the expression of vascular cell adhesion molecule-1 (VCAM-1) (S G Han, Eum, Toborek, Smart, & Hennig, 2010), endothelial-derived monocyte chemoattractant protein-1 (MCP-1) (Majkova, Smart, Toborek, & Hennig, 2009), and interleukin-6 (IL-6) (Hennig et al, 2002). Other groups have shown that PCBs impair endothelium-dependent dilation (Helyar et al, 2009) and promote obesity-associated atherosclerosis (Arsenescu, Arsenescu, King, Swanson, & Cassis, 2008).…”