Potential Role of Endotoxin as a Proinflammatory Mediator of Atherosclerosis

Abstract

Abstract-Atherosclerosis is increasingly recognized as a chronic inflammatory disease. Although a variety of inflammatory markers (ie, C-reactive protein) have been associated with atherosclerosis and its consequences, it is important to identify principal mediators of the inflammatory responses. One potentially important source of vascular inflammation in atherosclerosis is bacterial endotoxin. Mutations in Toll-like receptor 4 (TLR-4), an integral component of the endotoxin signaling complex, are fairly common in the Caucasian population and have recently been associated with reduced incidence of atherosclerosis and other cardiovascular diseases in some studies. Moreover, epidemiological studies suggest that endotoxemia at levels as low as 50 pg/mL constitutes a strong risk factor for the development of atherosclerosis. Endotoxin concentrations in this range may be produced by a variety of common subclinical Gram-negative infections. In this article, we outline the main elements of the endotoxin signaling receptor complex that initiates proinflammatory signaling (lipopolysaccharide binding protein [LBP], CD14, TLR-4, and MD-2) and discuss how changes in expression of these molecules may affect proatherogenic responses in the vessel wall. We also describe some of the proinflammatory effects of endotoxin that may be relevant to atherosclerosis, and discuss how serum lipoproteins, especially high-density lipoprotein, may modulate endotoxin-induced inflammatory responses. Further, we discuss recent findings suggesting that the lipid-lowering statins may have an additional protective role in blocking at least some of these proinflammatory signaling pathways. Finally, we discuss species diversity with regard to endotoxin signaling that should be considered when extrapolating experimental data from animal models to humans. I n recent years, there has been an increasing recognition of the link between inflammation and atherosclerosis. [1][2][3][4][5][6][7][8] Although markers of chronic inflammation, such as C-reactive protein, are clearly predictive of clinical atherosclerosis, 9,10 the sources of inflammatory responses, and the mechanisms by which inflammation leads to vascular disease, remain to be elucidated. One potentially important source of inflammation is endotoxin (lipopolysaccharide [LPS]), a unique glycolipid that comprises most of the outer leaflet of the outer wall of Gram-negative bacteria (GNB). [11][12][13][14][15] This complex molecule, found exclusively in GNB, consists of a highly variable carbohydrate portion and a unique lipid A region that is highly conserved across many GNB species. Gram-negative organisms colonize the human gastrointestinal, genitourinary, and respiratory tracts and generate endotoxin not only during overt infections but also in common subclinical or chronic conditions such as periodontitis, sinusitis, bronchitis, or diverticulitis. 16 -18 Even in apparently healthy individuals, endotoxin can be detected in human plasma. The Bruneck study provided the first epidemiological e...

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…The Bruneck study by Wiedermann et al in 1999 provided the first epidemiological evidence in support of a clinical association between levels of LPS and cardiovascular risk (145,146). Consistent with these findings, the role of bacterial endotoxin as a proinflammatory mediator of atherosclerosis has been widely reported for the HIVuninfected population (143). Studies on the role of bacterial bioproducts (i.e., LPS) and macrophage activators (sCD14) in the pathogenesis of atherosclerosis in HIV disease are under way, and discordant results have been generated so far.…”

“…The reasons for this phenomenon are likely complex, although recent studies suggested that chronic inflammation and immune activation/senescence may contribute to the initiation and progression of atherosclerosis in HIV infection (37,(140)(141)(142). LPS represents an important source of inflammatory stimuli (143) and has been investigated in the setting of atherosclerosis (144). The Bruneck study by Wiedermann et al in 1999 provided the first epidemiological evidence in support of a clinical association between levels of LPS and cardiovascular risk (145,146).…”

Rap1 induces cytokine production in pro-inflammatory macrophages through NFκB signaling and is highly expressed in human atherosclerotic lesions

“…[25][26][27][28] Given the involvement of NFkB signaling in atherosclerosis, LPS was used to activate it and stimulate the production of NFkBdependent pro-inflammatory cytokines. 29,30 Indeed, LPS caused a sustained activation of p65 in THP-1 macrophages ( Fig.…”

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

“…Interestingly, LPS is found in the circulation of apparently healthy subjects [6,7] and its activity may be associated with highfat diet and dyslipidaemia. Infusion of triacylglycerol enhances LPS responses in humans, including the production of cytokines, suggesting that LPS can be locally released from lipoproteins in peripheral tissues through lipoprotein lipase action [8].…”