ABSTRACT
BACKGROUND: C-reactive protein (CRP) is significantly associated with cardiovascular diseases; however, whether CRP plays a causal role in coronary artery disease has yet to be determined. In addition, the relationship between CRP, atherosclerosis, and inflammation remains controversial. METHODS AND RESULTS: Serum interleukin (IL)-6, IL-1ß, and CRP levels were determined in 160 patients at time points around percutaneous coronary intervention (PCI) with drug-eluting stent implantation. The levels were found to be at peak at 24 h post-PCI and gradually declined to the level before PCI at day 30 post-PCI. These inflammation markers around PCI have no statistical difference in the different postdilation pressures (≤14, 14-18, and ≥18 atm) and stent number (1 and ≥2 stents) groups. Treatment of cultured human vascular smooth muscle cells (VSMCs) with a combination of IL-6 and IL-1ß at concentrations associated with PCI did not result in any significant change in the CRP mRNA levels. The IL-6-augmented CRP expression in human internal mammary arteries (IMAs) stretched with a mechanical strength of 3 g was blocked by the nuclear factor-κB (NF-κB) peptide inhibitor SN50 and not by the inactive SN50 analog SN50M. IL-6 treatment increased NF-κB activity in human IMAs stretched with 3 g, and this effect was further blocked by stretch-activated channel (SAC) inhibitors (streptomycin or GdCl3) and SN50. CONCLUSIONS: The current study provides evidence that increased serum IL-6, IL-1ß, and CRP levels around PCI are not different between different postdilation pressure and stent number groups. The combination of IL-6 and IL-1ß at concentrations associated with PCI cannot induce CRP expression in human VSMCs, but they can augment mechanical strain-induced CRP synthesis via the SAC-NF-κB pathway in human IMAs.
Subject(s)
C-Reactive Protein/metabolism , Coronary Artery Disease/therapy , Inflammation Mediators/blood , Interleukin-1beta/blood , Interleukin-6/blood , Aged , Angioplasty, Balloon, Coronary/instrumentation , C-Reactive Protein/genetics , Cells, Cultured , Coronary Artery Disease/blood , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/genetics , Drug-Eluting Stents , Female , Gene Expression Regulation , Humans , Ion Channel Gating , Ion Channels/metabolism , Male , Mammary Arteries/metabolism , Mechanotransduction, Cellular , Middle Aged , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , NF-kappa B/metabolism , Pressure , Stress, Mechanical , Time FactorsABSTRACT
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.