Purpose Peroxisome proliferator-activated receptor gamma (PPARg) activation prevents atherosclerotic vascular disease and reduces vascular dysfunction and inflammation in diabetic and nondiabetic subjects. The precise molecular mechanisms for this vascular protection remain to be defined. We have previously shown that PPARg ligands enhance endothelial nitric oxide (NO) bioavailability, in part, by reducing superoxide anion (O2 2.) generation and suppressing expression of selected subunits of NADPH oxidase and by enhancing eNOS activity at the level of post-translational regulation. We hypothesized that PPARg-induced increases in endothelial NO production contribute to previously described vascular anti-inflammatory effects following PPARg activation.
Methods Human umbilical vein endothelial cells (HUVECs) were treated with 10 μM 15d-PGJ2 with or without human recombinant TNFa (100 U for 2 hours) followed by analysis of cytokine production, adhesion molecule expression, and monocyte adhesion. In separate studies, HUVECs were treated with the NOS inhibitor L-NAME prior to treatment with PPARg ligands.
Results 15d-PGJ2 attenuated TNFa-mediated induction of IL-6, IL-8, MCP-1, and IP-10, endothelial-monocyte adhesion, and ICAM, VCAM, and E-selectin expression. The NOS inhibitor L-NAME reduced 15d-PGJ2-mediated NO production and attenuated 15d-PGJ2 repression of TNFa-mediated ICAM expression.
Conclusions These data indicate that treatment with 15d-PGJ2 suppressed TNFa-stimulated expression of inflammatory genes in vascular endothelial cells. L-NAME-mediated attenuation of the ability of 15d-PGJ2 to suppress ICAM expression suggests that PPARg-stimulated NO production may contribute to the anti-inflammatory effects of PPARg ligands in vascular endothelial cells.
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