Interleukin 6 augments mechanical strain-induced C-reactive protein synthesis via the stretch-activated channel-nuclear factor κ B signal pathway.

OBJECTIVES: C-reactive protein (CRP), an inflammation marker, is a strong independent risk factor for cardiovascular disease. Vessels are able to express CRP; however, the molecular mechanism behind this expression is not clear. METHODS: Reverse transcription PCR and ELISA were used to detect messenger RNA and proteins of CRP and nuclear factor κB (NF-κB) activity in vessel rings stretched with different mechanical strains. RESULTS: Interleukin (IL)-6 treatment did not induce CRP expression in vessel rings of white rabbits in the absence of mechanical strain. In contrast, IL-6 augmented CRP expression in vessel rings stretched with mechanical strains of 3 and 5 g (CRP mRNA, IL-6: 11.367±1.68 and 12.78±0.76 vs vehicle: 7.27±0.88 and 8.3±0.91 folds, respectively; CRP, IL-6: 12.79±1.62 and 14.05±2.1 vs vehicle: 7.72±1.04 and 8.16±1.52 folds, respectively; p<0.05 vs 0 g group and vehicle control group; n=5), and this effect was completely blocked by treatment with gadolinium III chloride hexahydrate (GdCl3). Moreover, IL-6 treatment increased NF-κB activity in vessels stretched with a mechanical strain of 3 g, and this effect was blocked by stretch-activated channel inhibitors (streptomycin or GdCl3) and the NF-κB peptide inhibitor SN50, but not by the inactive SN50 analogue SN50M. We also performed similar experiments on human internal mammary arteries and obtained similar results. CONCLUSIONS: These results indicate that the inflammatory cytokine IL-6 alone does not induce CRP synthesis in vessels in the absence of mechanical strain; however, IL-6 augments mechanical strain-induced CRP synthesis in vessels via the stretch-activated channel-NF-κB pathway.

Mechanical strain induces expression of C-reactive protein in human blood vessels.

C-reactive protein (CRP) is a powerful independent risk factor for cardiovascular diseases. Elevated mechanical strain on vessels induces the local expression of proinflammatory cytokines. We hypothesized that mechanical strain on vessels may induce local CRP expression. Human saphenous vein and internal mammary artery (IMA) rings were stretched in vitro with a mechanical strength of 1, 3, or 5 g. Reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay results showed that mechanical stretching significantly induced CRP mRNA and protein expression in the saphenous vein and IMA rings in a strength-dependent manner reaching a maximum at a mechanical strength of 3 g, but CRP expression returned at strengths of >5 g. In vessels, mechanical strain-induced CRP expression was blocked by two stretch-activated ion channel (SAC) blockers: GdCl(3) and streptomycin. Mechanical strain also increased activation of nuclear factor kappaB (NF-kappaB), which was detected with a nonradioactive NF-kappaB p50/p65 EZ-TFA transcription factor assay. Mechanical strain-induced NF-kappaB activation was blocked by SAC blockers and the NF-kappaB inhibitor (SN50, H-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu-Ala-Pro-Val-Gln-Arg-Lys-Arg-Gln-Lys-Leu-Met-Pro-OH). SN50 also blocked mechanical strain-induced CRP expression in vessels. In conclusion, mechanical strain induces CRP expression in IMAs and saphenous veins by activating the SAC-induced NF-kappaB pathway.