Critical vascular
inflammation leads to vascular dysfunction and
cardiovascular diseases, including
abdominal aortic aneurysms,
hypertension, and
atherosclerosis.
Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-
inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of
andrographolide in vascular smooth muscle cells (VSMCs) exposed to a proinflammatory stimulus,
tumor necrosis factor-α (TNF-α). Treating TNF-α-stimulated VSMCs with
andrographolide suppressed the expression of
inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced
c-Jun N-terminal kinase (JNK), Akt, and p65 phosphorylation was observed in
andrographolide-treated VSMCs. However,
andrographolide affected neither IκBα degradation nor
p38 mitogen-activated protein kinase or
extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with
LY294002, a
phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with
SP600125, a JNK inhibitor, markedly reversed the
andrographolide-mediated inhibition of p65 phosphorylation. In addition,
LY294002 and
SP600125 both diminished Akt phosphorylation, whereas
LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using
andrographolide can benefit the treatment of vascular inflammatory diseases, and
andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.