Complex cellular and inflammatory interactions are involved in the progress of vascular diseases. Endothelial cells, upon exposure to cytokines, undergo profound alterations of function that involve gene expression and de novo protein synthesis. The functional reprogramming of endothelial cells by cytokines is of importance especially in patients with chronic vascular inflammation. The intercellular network of dendritic cells, T-lymphocytes, macrophages and smooth muscle cells generates a variety of stimulatory cytokines [e.g. TNF-alpha (tumour necrosis factor-alpha), IL (interleukin)-1, IL-6 and IFN-gamma (interferon-gamma)] and growth factors that promote the development of functional and structural vascular changes. High concentrations of proinflammatory cytokines increase oxidative stress, down-regulate eNOS (endothelial nitric oxide synthase) bioactivity and induce endothelial cell apoptosis. Chemoattractant cytokines [e.g. VEGF (vascular endothelial growth factor), TGF-beta1 (transforming growth factor-beta1) and IL-8] are important regulators of inflammation-induced angiogenesis and are directly modulated by nitric oxide. This review will focus on the vascular mechanisms orchestrated by cytokines and summarizes the current knowledge concerning the contribution of cytokines to cardiovascular diseases.

Background— Atherosclerosis is an inflammatory disease in which monocytes and macrophages have been suggested to play an essential role. The underlying signaling mechanisms are unknown thus far. We hypothesized that the human isoform of Toll-like receptor (hTLR)-4 is involved in monocyte activation of patients with accelerated forms of atherosclerosis. Methods and Results— Expression of hTLR4 on circulating monocytes from 30 controls, 20 patients with stable angina (SA), 40 patients with unstable angina (UA), and 28 patients with acute myocardial infarction (AMI) was compared with the use of flow-cytometry and reverse transcription–polymerase chain reaction. Regulation of interleukin (IL)-12 and B7-1 as downstream events of TLR4 activation was analyzed after lipopolysaccharide stimulation of monocytes. TLR4-transfected Chinese hamster ovary (CHO) cells were used to identify potential hTLR4 ligands in the serum of patients with UA or AMI. Circulating hTLR4 + /CD14 + monocytes were ≈2.5-fold increased above controls and patients with SA in the UA and AMI groups ( P <0.0001). This was paralleled by enhanced transcript levels of TLR4 and Myd88 in patients with UA and AMI ( P <0.0001) and increased expression of IL-12 (UA 35.5±7.8, AMI 31.8±7.7 versus SA 2.2±0.5, controls 2.1±0.3 pg/mL; P <0.0002) and B7-1 (UA 27.3±14.4, AMI 22.6±11.1 versus SA 3.4±2.5, controls 2.4±2.3%; P <0.0001). Compared with serum from patients with UA and AMI, challenging TLR4-transfected CHO cells with serum from SA patients yielded only a weak response ( P <0.0001). Coincubation with anti–heat shock protein 60 inhibited CHO cell activation. Conclusions— UA and AMI are associated with enhanced expression and signaling events downstream of hTLR4 in circulating monocytes. These observations suggest hTLR4 activation as a signaling mechanism in immune-mediated progression of atherosclerosis.

Objective-Anti-inflammatory effects of statins contribute to their clinical benefit. Molecular mechanisms underlying these effects have not been well explored. Because statins attenuate lipopolysaccharide (LPS) responsiveness, we hypothesized that part of the pleiotropic effects are mediated through innate immunity. Methods and Results-Toll-like receptor (TLR) 4 expression and downstream signaling in CD14 ϩ monocytes after incubation with simvastatin and atorvastatin were quantified via flow-cytometry, quantitative RT-PCR, kinase assay, and enzyme-linked immunosorbent assay. Incubation with intermediates/ inhibitors of the mevalonate pathway was used to identify the mode of statin action. Statin incubation resulted in a dose-dependent reduction of TLR4 expression (53Ϯ7.6% reduction compared with untreated monocytes; PϽ0.005), transcript levels (68Ϯ6.3%; PϽ0.002), decreased IRAK phosphorylation (37Ϯ8.3%; PϽ0.05), and LPS-induced IL-6, IL-12, tumor necrosis factor (TNF)-␣, and B7-1 expression (PϽ0.05). Four weeks of treatment with atorvastatin significantly reduced TLR4 expression on circulating CD14 ϩ monocytes by 36.2Ϯ4.2% (PϽ0.05). Effects of statins were reversed by mevalonate (Pϭ0.57). Incubation with specific inhibitors of geranylgeranyltransferase (54Ϯ4.3%), farnesyltransferase (57Ϯ5.1%), or with clostridium-difficile toxin B (58Ϯ6.1%, PϽ0.01) imitated the statin effects. Whereas wortmannin and LY294002 inhibited the statin effect (Pϭ0.27), incubation with a specific RhoA kinase inhibitor had no effect (Pϭ0.57). Toll-like receptors (TLRs) were identified as key recognition components of pathogen-associated molecular patterns in mammals. Recently, TLR4 was identified as the signaling receptor for LPS. 9 Activation of TLR4 is followed by interaction with MyD88 and TOLLIP, subsequent autophosphorylation of IRAK, and association with TRAF-6. Finally, activation of NF-B and members of the extracellular signalregulated kinase and SAPK/JNK and p38 MAP kinases is followed by upregulation of MHC expression and expression of costimulatory molecules (eg, B7-1 and B7-2) and proinflammatory cytokines (eg, IL-1␤, IL-6, IL-12, TNF-␣). 10 -12 Accordingly, several reports suggest an important role of TLR4 in cardiovascular disease. [13][14][15] We hypothesized that part of the pleiotropic statin effects are mediated through innate immune mechanisms. The goal of our study was to investigate the impact of statins on expression of TLR4 in CD14 ϩ monocytes and to explore their effect on TLR4-dependent downstream signaling ex vivo. Conclusions-Statins

Orthogonal polarization spectral imaging revealed no major changes of microvascular perfusion during uncomplicated hypothermic CPB. The slightly reduced functional capillary density during CPB may be caused by several factors all present during CPB, including hypothermia, the artificial extracorporeal perfusion, surgical trauma, hemodilution, and inflammatory reaction. The current data do not allow differentiation between the effects of those possible causes.

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