Antioxidants Inhibit JNK and p38 MAPK Activation but not ERK 1/2 Activation by Angiotensin II in Rat Aortic Smooth Muscle Cells.

Abstract

Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) hypertrophy, which results in several cardiovascular diseases. Ang II-induced cellular events have been mediated, in part, by reactive oxygen species (ROS) which also involve activation of mitogen-activated protein (MAP) kinases. Although it has been proposed that the therapeutic administration of antioxidants is useful for vascular diseases, the precise mechanisms which regulate ROS-sensitive signaling events have not been well characterized. Thus, we hypothesized that antioxidants may affect ROS-mediated MAP kinases activation induced by Ang II. The present findings showed that Ang II stimulated rapid and significant activation of ERK 1/2, JNK and p38 MAPK in cultured rat aortic smooth muscle cells (RASMC). Ang II-induced ERK 1/2 activation was not affected by all antioxidants examined, whereas JNK was sensitive to all antioxidants. In contrast, p38 MAPK activation was inhibited by DPI and ascorbic acid concentration-dependently, but by NAC only at high concentration. DETC and Trolox C had no effects on p38 MAPK activation by Ang II. We further examined the effects of antioxidants on Ang II-induced increases in oxygen consumption as an index of ROS generation in RASMC. DPI strongly inhibited Ang II-induced increases in oxygen consumption. DETC also inhibited Ang II-induced oxygen consumption, whereas ascorbic acid markedly augmented it. These findings suggest that the inhibitory effects of antioxidants on MAP kinases activation in VSMC are attributable, in part, to their modulating effects on ROS generation by Ang II in VSMC. Thus, inhibition of MAP kinases by antioxidants may imply their usefulness for relief of cardiovascular diseases.

The Role of Big Mitogen-Activated Protein Kinase 1 (BMK1) / Extracellular Signal-Regulated Kinase 5 (ERK5) in the Pathogenesis and Progression of Atherosclerosis

“…Because transfection with nox-1antisense oligonucleotides inhibited the effect of Ang II-induced superoxide generation and serum-induced VSMC proliferation (13,16), it was suggested that nox-1 is an important subunit of the NADH/NADPH oxidase in VSMCs. In an electron paramagnetic resonance (EPR) study, we also demonstrated that Ang II and endothelin stimulate • OH radical generation in VSMCs and that treatment with antioxidants inhibit these effects (17).…”

Increased responsiveness to JNK1/2 mediates the enhanced H2O2-induced stimulation of Cl−/HCO3− exchanger activity in immortalized renal proximal tubular epithelial cells from the SHR

“…In fact, H 2 O 2 has been demonstrated to stimulate the activity of other transporters, namely NHE and Na/K/2Cl. NHE from Wistar [25] and SpragueDawley rat ventricular myocytes [26] were stimulated after exposure of cells to [38,39]. We previously showed that the increased intracellular H 2 O 2 in SHR PTE cells was attenuated when cells were cultured in medium supplemented with apocynin (a NADPH oxidase inhibitor) while in WKY PTE cells no effect was observed [20].…”

Inhibition of NF-κB and Oxidative Pathways in Human Dendritic Cells by Antioxidative Vitamins Generates Regulatory T Cells

“…Vitamin E is known to inhibit the p38 MAPK pathway in smooth muscle cells (73). Treatment with vitamin C alone enhanced the expression of phosphorylated p38 MAPK in murine melanoma cells due to an increase in intracellular region of interest levels (33).…”