Peroxisome proliferator-activated receptor-γ activation reduces cyclooxygenase-2 expression in vascular smooth muscle cells from hypertensive rats by interfering with oxidative stress.

AIMS: Hypertension is associated with increased plasma inflammatory markers such as cytokines and increased vascular cyclooxygenase-2 (COX-2) expression. The ability of peroxisome proliferator-activated receptor-γ (PPARγ) agonists to reduce oxidative stress seems to contribute to their anti-inflammatory properties. This study analyzes the effect of pioglitazone, a PPARγ agonist, on interleukin-1β-induced COX-2 expression and the role of reactive oxygen species (ROS) on this effect.

METHODS AND RESULTS: Vascular smooth muscle cells from hypertensive rats stimulated with interleukin-1β (10 ng/ml, 24 h) were used. Interleukin-1β increased: 1) COX-2 protein and mRNA levels; 2) protein and mRNA levels of the NADPH oxidase subunit NOX-1, NADPH oxidase activity and ROS production; and 3) phosphorylation of inhibitor of nuclear factor kappa B (IκB) kinase (IKK) nuclear expression of the p65 nuclear factor kappa B (NF-κB) subunit and cell proliferation, all of which were reduced by apocynin (30 μmol/l). Interleukin-1β-induced COX-2 expression was reduced by apocynin, tempol (10 μmol/l), catalase (1000 U/ml) and lactacystin (5 μmol/l). Moreover, H2O2 (50 μmol/l, 90 min) induced COX-2 expression, which was reduced by lactacystin. Pioglitazone (10 μmol/l) reduced the effects of interleukin-1β on: 1) COX-2 protein and mRNA levels; 2) NOX-1 protein and mRNA levels, NADPH oxidase activity and ROS production; and 3) p-IKK, p65 expressions and cell proliferation. Pioglitazone also reduced the H2O2-induced COX-2 expression and increased Cu/Zn and Mn-superoxide dismutase protein expression. PPARγ small interfering RNA (5 nmol/l) further increased interleukin-1β-induced COX-2 and NOX-1 mRNA levels. In addition, pioglitazone increased the interleukin-1β-induced PPARγ mRNA levels.

CONCLUSION: PPARγ activation with pioglitazone reduces interleukin-1β-induced COX-2 expression by interference with the redox-sensitive transcription factor NF-κB.