interleukin-8 and cerivastatin

The aim of our study was to evaluate whether a single dose of cerivastatin at the time of admission of patients with unstable angina pectoris (UAP) or non-Q-wave myocardial infarction (NQMI) can influence the serum level of C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-8 (IL-8) 24 h later. Forty-four patients with rest chest pain and subendocardial ischemia on ECG were randomized to receive cerivastatin 0.3 mg at the time of admission (group C+) to standard therapy or to remain just on standard therapy (group C-). Blood samples for determination of troponin I (TI), CRP, IL-6 and IL-8 were collected at admission (entry level) and 24 h later (final level). Patients with non-physiological baseline levels of TI, as well as patients with progression to Q wave MI were excluded. All baseline, clinical and demographic data and final values of TI were comparable in the two groups. In patients treated with cerivastatin (group C+, n = 13) we observed decrease in the CRP level (-6.73 +/- 3.93 mg/L); on the other hand, in group C- (n = 17) the CRP level increased (+7.92 +/- 2.77 mg/L, p = 0.004). Similar differences were observed also in IL-6: in group C+ the level was significantly reduced as compared with the increase in group C- (-0.76 +/- 0.52 vs. 4.58 +/- 1.49 ng/L, p = 0.005). The level of IL-8 was not affected. Our results suggest that early treatment with cerivastatin can decrease the serum level of CRP and IL-6 in patients with UAP/NQMI; this might positively influence their prognosis. Nevertheless, further studies are needed to support this hypothesis.

Topics: Aged; Angina, Unstable; C-Reactive Protein; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Pyridines

Interleukin-8 (IL-8) is a potent chemotactic factor that has been implicated in atherogenesis. HMG-CoA reductase inhibitors (statins) may reduce the cardiovascular risk and vulnerability of atherosclerotic plaque through nonlipid mechanisms such as inhibition of cytokine expression. In this study, we investigated the effects of statins on IL-8 synthesis in human vascular smooth muscle cells (VSMCs). Addition of angiotensin II (Ang II) increased IL-8 production in VSMCs in a time (0-24 h)- and dose (10(-8)-10(-6) mol/l)-dependent manner with increased IL-8 mRNA accumulation. The Ang II type 1 receptor (AT1R) antagonist candesartan, but not the Ang II type 2 receptor (AT2R) antagonist PD123319, significantly blocked Ang II-induced IL-8 production. Addition of fluvastatin decreased the basal and Ang II-induced IL-8 production in VSMCs in a dose (10(-8)-10(-5) mol/l)-dependent manner with a decrease in IL-8 mRNA accumulation. The effect of fluvastatin on IL-8 production was completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not in the presence of squalene or farnesyl-pyrophosphate. Lipophilic cerivastatin also significantly decreased IL-8 production, while hydrophilic pravastatin showed no effect on IL-8 levels. In conclusion, we demonstrated for the first time that Ang II increased IL-8 production and fluvastatin decreased the basal and Ang II-induced IL-8 production in human VSMCs. These findings suggested that Ang II may exacerbate atherosclerosis through induction of IL-8 in VSMCs, while statins may exert therapeutic effects by modulating IL-8 synthesis in patients with atherosclerotic disease.

Topics: Analysis of Variance; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Interleukin-8; Muscle, Smooth, Vascular; Pravastatin; Probability; Pyridines; RNA, Messenger; Sensitivity and Specificity

Blood levels of cytokines are commonly elevated in severe congestive heart failure (CHF) and in coronary artery disease (CAD). While the adverse effects of cytokines on contractile function and myocardial cell integrity are well studied, little is known on whether cardiac cells are only targets or active players in these inflammatory reactions.. We tested if human coronary artery endothelial cells (HCAEC) may become a source of cytokine and adhesion molecule expression when stimulated with bacterial lipopolysaccharide (LPS). Analysis of HCAEC supernatants by ELISA identified enhanced secretion of IL-6, IL-8, and MCP-1 while endothelin-1 was not increased. IL-1beta, IL-10, or TNF-alpha were not detectable by ELISA while RT-PCR revealed enhanced mRNA expression of IL-1beta and TNF-alpha but not IL-10. FACS analysis showed an LPS-induced upregulation of ICAM-1, VCAM, and ELAM-1. LFA-1 could not be detected. We further characterized receptors involved in LPS-induced signaling. Our results indicate that activation of HCAEC by LPS requires Toll-like receptor (TLR) 4. Pretreating the cells with the 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase inhibitor Cerivastatin reduced IL-6 release.. Taken together, our results indicate that activated HCAEC may act as inflammatory cells and thus directly contribute to the progression of CHF and CAD.

Topics: Cell Adhesion Molecules; Cells, Cultured; Chemokine CCL2; Coronary Vessels; Cytokines; Drosophila Proteins; E-Selectin; Endothelium, Vascular; Glycolipids; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-6; Interleukin-8; Lipid A; Lipopolysaccharides; Membrane Glycoproteins; Pyridines; Receptors, Cell Surface; RNA, Messenger; Stimulation, Chemical; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1