Atherosclerosis is a leading cause of mortality and morbidity in the western world. It has been recognized for over a century, and the understanding of its pathogenesis has undergone many changes. Pathophysiological studies have unravelled the interactions of molecular and cellular elements involved in atherogenesis. The focus has shifted to the novel risk factors as well as characteristics and stability of atherosclerotic plaque; the genetic predisposition has further broadened the pathogenetic mechanisms. This review focuses on the molecular mechanisms involved in the evolution of the atherosclerotic plaque that may pave the way for selecting optimal therapies and preventing plaque complications. Atherosclerosis is no longer a disease attributed mainly to the high lipid content of the body. New insight into the disease pathology has shown it to be a disease of much greater ramifications. Endothelial damage and reactive oxygen species (and other free radicals) have predominantly emerged as factors in virtually all pathways leading to the development of atherosclerosis due to hyperlipidemia, diabetes, hypertension or smoking. Novel risk factors such as hyperhomocysteinemia, infections and systemic lupus erythematosus have emerged. Atherosclerosis has come to be regarded as a chronic inflammatory disease with an autoimmune component. The genetic basis of the disease assumes significance as candidate genes are identified and gene therapy becomes a promising new addition to the existing, less substantial conventional therapies.

Pathogenesis of atherosclerosis: A multifactorial process.

The systematic review was commissioned by the Australian National Health and Medical Research Council (NHMRC) to evaluate the scientific literature relating to the health effects of fluoride and fluoridation. The systematic review's research questions relate to the caries-reducing benefits and associated potential health risks of providing fluoride systemically (via addition to water, milk and salt) and the use of topical fluoride agents, such as toothpaste, gel, varnish and mouthrinse. Although the review summarises the recent evidence, it does not constitute health policy or clinical practice recommendations. A literature search was undertaken using the Medline and Embase databases (via www.embase.com
 ). In addition, the Cochrane Systematic Review and Clinical Trial databases were searched to help identify additional systematic reviews and original studies. Because of the availability of recent systematic reviews, searches were limited to publications from 1996 onwards . The search was conducted in December 2006 and limited to English-language publications. Based on types of intervention (individual or population) and the outcomes assessed (efficacy or safety), the hierarchy of study types considered most relevant for answering each of the clinical questions defined in this review was chosen (Table 1). The levels of evidence used by NHMRC for intervention and aetiological studies are summarised in Table 2.
 Screening of eligible studies was conducted by three reviewers. Data were extracted for all of the included systematic reviews and individual studies using standardised data-extraction forms. This included information about the study design, NHMRC level of evidence, population, intervention, comparator, outcome definitions and results. Information relating to potential biases and study quality were also extracted. Where appropriate, study results were pooled using standard meta-analysis techniques. In total, 5418 nonduplicate citations were identified. After applying the inclusion and exclusion criteria, 408 citations were considered potentially eligible for inclusion in the review. After the review of the full papers of potentially eligible articles, 77 citations were included in the review. The summary of findings was presented in the context of the research questions (Table 3).
 Fluoridation of drinking water remains the most effective and socially equitable means of achieving community-wide exposure to the caries prevention effects of fluoride. It is recommended (see also www.nhmrc.gov.au/news/media/rel07/_files/fluoride_flyer.pdf
 ) that water be fluoridated in the target range of 0.6–1.1 mg/l, depending on the climate, to balance reduction of dental caries and occurrence of dental fluorosis.n particular with reference to care in hospital for those following stroke.

/pdf/a-systematic-review-of-the-efficacy-and-safety-of-l84tk2wkvy.pdf

A systematic review of the efficacy and safety of fluoridation

Objective: 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. Methods and results: 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-1β, IL-10, or TNF-α were not detectable by ELISA while RT-PCR revealed enhanced mRNA expression of IL-1β and TNF-α 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. Conclusions: Taken together, our results indicate that activated HCAEC may act as inflammatory cells and thus directly contribute to the progression of CHF and CAD.

TLR4-mediated inflammatory activation of human coronary artery endothelial cells by LPS

Adrenomedullin (AM) is a potent vasorelaxant peptide recently identified in extracts of pheochromocytoma. We have found that AM is actively secreted from endothelial cell (EC) and vascular smooth muscle cell (VSMC). To elucidate the function of AM secreted from EC, the effects of 43 substances on secretion of AM from cultured rat EC were examined in this study. We first confirmed that synthesized AM was not stored but constitutively secreted from EC, indicating that the amount secreted could be used as an index of AM synthesis in EC. EC secreted AM at a rate 5.8 times higher than VSMC, and AM gene transcription in EC significantly contributed to the total aortic AM messenger RNA. Tumor necrosis factor, interleukin-1, and lipopolysaccharide augmented AM secretion from EC, showing cooperative effects, which suggests that AM secreted from EC participates in the induction of hypotension in septic shock. Transforming growth factor beta1 and FCS suppressed AM secretion but stimulated endothelin-1 (ET-1) secretion. Thrombin potently stimulated AM secretion from EC but suppressed it from VSMC. Thyroid hormone and phorbol ester increased AM and ET-1 secretion but to a lesser extent. Interferon-gamma inhibited AM secretion from EC, whereas oxidized LDL stimulated it. Regulation of AM production in EC is found to be similar to that of VSMC with several exceptions, but AM and ET-1 production in EC are deduced to be controlled independently and by different mechanisms. AM stimulates cAMP production in EC, though receptors expressed on cultured rat EC are not specific to AM but to calcitonin gene-related peptide. Based on these findings, AM production in EC is thought to be regulated by a variety of substances coming from blood and neighboring cells, and the secreted AM is deduced to dilate blood vessels as an endothelium-derived relaxing factor competing with ET-1.

/pdf/regulation-of-adrenomedullin-production-in-rat-endothelial-lqzlhzlfsa.pdf

Regulation of adrenomedullin production in rat endothelial cells.

Obesity-linked insulin resistance is associated with chronic inflammation and cardiovascular complications. Free fatty acids (FFAs) are prominent candidates for the molecular link between these disorders. In this study, we determined whether FFAs contribute to vascular inflammation via induction of interleukin (IL)-6 in coronary artery endothelial cells (CAECs) and coronary artery smooth muscle cells (CASMCs) and whether this is reflected in vivo. In contrast to our findings regarding IL-6 and gp130 (the glycoprotein of 130 kDa) expression, IL-6 receptor mRNA expression was very low in these cells. Palmitate, but not linoleate, induced a significant increase in IL-6 mRNA expression in CAECs (P < 0.001) and, to a less relevant extent, in CASMCs (P < 0.01). gp130 remained unaffected. As to potency, palmitate was comparable with the IL-6-inducer IL-1beta. To substantiate our in vitro data, we examined the plasma FFA pattern in 54 healthy human subjects and studied the relation of individual FFAs with plasma IL-6. IL-6 levels correlated with palmitate, but not with other abundant FFAs, even after adjusting for body fat (r = 0.33, P < 0.05) and total FFAs (r = 0.29, P < 0.05). We show here that the common plasma FFA palmitate induces high levels of IL-6 in CAECs. Furthermore, palmitate correlates with IL-6 in vivo. This points to a potential contribution of palmitate to vascular inflammation.

https://diabetes.diabetesjournals.org/content/diabetes/53/12/3209.full.pdf

Palmitate-Induced Interleukin-6 Expression in Human Coronary Artery Endothelial Cells

Mast cells (MC) are strategically located along blood vessels and, on activation, exocytose granules that contain many vasoactive mediators. Endothelial cell (EC) activation, which includes the production of such cytokines as interleukin-6 (IL-6) and IL-8, is a key event in vascular inflammation. In this study, the effects of purified MC granules (MCG) on the production of IL-6 and IL-8 by human coronary artery EC (HCAEC) were examined. HCAEC were cocultured with MCG in the presence or absence of lipopolysaccharide (LPS), and IL-6 and IL-8 levels in the culture medium were assayed by ELISA. Unactivated HCAEC produced only low levels of IL-6 or IL-8, and the addition of MCG alone resulted in little or no increase in production of these cytokines. LPS-activated HCAEC produced significant amounts of IL-6 and IL-8 in a dose-dependent and time-dependent fashion, which was amplified 2–3-fold by MCG at EC/MC ratios of 16:1–2:1. Scanning electron microscopy revealed direct communication between MCG and HCAEC. The...

Endotoxin and mast cell granule proteases synergistically activate human coronary artery endothelial cells to generate interleukin-6 and interleukin-8.

Mast cells are constituent cells of vascular tissue and their numbers are increased in atherosclerotic vessels. To gain insight into the role of mast cells in vascular inflammation, the effect of mast cell granules (MCG) on endothelial cell production of interleukin-6 (IL-6) was examined. Human umbilical vein endothelial cells (HUVEC) were cultured with lipopolysaccharide (LPS) in the presence or absence of rat peritoneal MCG and IL-6 production was assayed by enzyme-linked immunosorbent assay. The interaction of MCG with HUVEC in culture was examined by electron microscopy (EM). The EM studies revealed that MCG are internalized by HUVEC and appear intact even after 24 h in culture. Unactivated HUVEC produced little or no IL-6 either in the presence or absence of MCG. Treatment of HUVEC with LPS stimulated IL-6 production in a dose- and time-dependent fashion. Addition of MCG to LPS-activated HUVEC-resulted in the potentiation of IL-6 production at all LPS doses. MCG-induced enhancement of IL-6 production was evident even at a mast cell-to-endothelial cell ratio of 1:32. The enhancement of IL-6 production by MCG was also seen when tumor necrosis factor alpha was used as an activator. Although potentiation was evident when MCG were added 6 h before or after LPS stimulation, the maximum effect was noted when MCG and LPS were added simultaneously. MCG-mediated enhancement of IL-6 production was abrogated by pretreating MCG with protease inhibitors. Although MCG proteases potentiate IL-6 production by HUVEC, they do not degrade secreted IL-6. These results demonstrate that MCG interact with endothelial cells and modulate the production of an important inflammatory cytokine.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1002/jlb.62.2.210

Mast cell granules potentiate endotoxin-induced interleukin-6 production by endothelial cells.

Mast cells are constituent cells of vascular tissue and their numbers are increased in atheroscie- rotic vessels. To gain insight into the role ofmast cells in vascular inflammation, the effect of mast cell granules (MCG) on endothelial cell production of interleukin-6 (IL-6) was examined. Human umbilical vein endothe- lial cells (HUVEC) were cultured with lipopolysaccha- ride (LPS) in the presence or absence ofrat peritoneal MCG and IL-6 production was assayed by enzyme- linked immunosorbent assay. The interaction of MCG with HUVEC in culture was examined by electron ml- croscopy (EM). The EM studies revealed that MCG are internalized by HIJVEC and appear intact even after 24 h in culture. Unactivated HUVEC produced little or no IL-6 either in the presence or absence of MCG. Treatment of HUVEC with LPS stimulated IL-6 production in a dose- and time-dependent fashion. Addition of MCG to LPS-activated HUVEC resulted in the potentiation ofIL-6 production at all LPS doses. MCG-induced enhancement of IL-6 production was evident even at a mast cell-to-endothelial cell ratio of 1:32. The enhancement of IL-6 production by MCG was also seen when tumor necrosis factor a was used as an activator. Although potentiation was evident when MCG were added 6 h before or after LPS stimulation, the maximum effect was noted when MCG and LPS were added simultaneously. MCG-mediated enhance- ment of IL-6 production was abrogated by pretreat- lag MCG with protease inhibitors. Although MCG pro- teases potentiate IL-6 production by HUVEC, they do not degrade secreted IL-6. These results demonstrate that MCG interact with endothelial cells and modulate the production ofan important inflammatory cytokine. J. Leukoc. Biol. 62: 210-216; 1997.

production by endothelial cells

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Endotoxin and mast cell granule proteases synergistically activate human coronary artery endothelial cells to generate interleukin-6 and interleukin-8.

Mast cell granules potentiate endotoxin-induced interleukin-6 production by endothelial cells.

production by endothelial cells