Low Level Endotoxemia LPS Theory of Coronary Artery Disease

The LPS theory of coronary artery disease is the idea that “Leaky Gut” is the direct cause of atherosclerosis by virtue of the LPS, endotoxin released into the blood stream which incites an inflammatory reaction in the endothelium.  LPS is short for LipoPolySacharride, the outer lipid coat of gram negative microbial organisms residing in the GI tract.  Studies show that a low level of endotoxemia is common in the population, and the level of LPS in the blood stream correlates with risk of cardiovascular disease.

Above Image is Fig 1 from Brown et al 2015. Schematic showing LPS originating from Leaky Gut, released into circulation activating macrophages and directly causing coronary artery disease. (4)

Prevent Leaky Gut to Prevent Vascular Disease

Various interventions to prevent leaky gut have been shown to also reduce progression of atherosclerosis. One such study from April 2016 by Dr Lin showed that in mice genetically engineered for accelerated atherosclerosis, treatment with a probiotic which restores the mucin barrier and prevents leaky gut also serves to reduce atherosclerosis.(1)  The authors state: The probiotic,“Akermansia muciniphila , attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier.”

According to Dr. Brown in a 2015 article (4), this circulating endotoxin is called “metabolic endotoxemia”, found to be prevalent in many chronic metabolic diseases such as obesity, type II diabetes, and atherosclerosis.(4) Increased intestinal permeability , leaky gut and low level endotoxemia has been implicated in Parkinson’s Disease, a neurodegenerative condition.(26-27)

Dr Lehr showed that endotoxin treated rabbits exhibited accelerated atherosclerosis.(5,6).  In Humans, the Bruneck study established low level endotoxemia and systemic inflammation as a strong predictor for atherosclerosis.(5,6)

Animal Models

The LPS induce animal model of atherosclerosis has emerged as a popular laboratory technique to test various interventions in mice genetically engineered for atherosclerosis (Apo-E mouse). (14)  Dr. Cuaz-Pérolin reported in a 2008 article that  weekly LPS injection in mice doubled the atherosclerotic plaque size.  Treatment with various anti-inflammatory botanicals (such as Boswellia) cut plaque size in half. (14)

Other Substances Beneficial in the LPS Apo-E Mouse Model for reducing plaque size:  Garlic (15) , Fish Oil (16), Liposomal Glutathione (17) ,  Anthocyanins from Sweet potato (18), Bilberry Extracts (19), Tocotrienol Vitamin E (20) ,  stress reduction (21) ,  Bee Venom (22), Vitamin C.

Conclusion:  Now that the cholesterol theory of atherosclerotic heart disease has been falsified, we are free to direct attention to the true cause of atherosclerotic vascular disease, leaky gut with low level endotoxemia and systemic inflammation.  Prevention of atherosclerosis should focus on interventions which block leaky gut and reduce low level endotoxemia, and the associated systemic inflammation.

If you liked this article, you might like my book, Heart Book (left cover image) at this link on Amazon.

 

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Links and references
LPS theory of atherosclerosis

1 ) Li J, Lin S, Vanhoutte PM, Woo CW, Xu A. Akkermansia muciniphila
protects against atherosclerosis by preventing metabolic endotoxemiainduced inflammation in Apoe-/- mice. Circulation. April 2016. pii:  CIRCULATIONAHA. 115.019645.
Background—Altered composition of the gut microbiota is involved in both the onset and progression of obesity and diabetes mellitus. However, the link between gut microbiota and obesity-related cardiovascular complications has not been explored. The present study was designed to investigate the role of Akkermansia muciniphila, a mucin-degrading bacterium with beneficial effects on metabolism, in the pathogenesis of atherosclerosis in apolipoprotein E–deficient (Apoe−/−) mice.

Methods and Results—Apoe−/− mice on normal chow diet or a Western diet were treated with A muciniphila by daily oral gavage for 8 weeks, followed by histological evaluations of atherosclerotic lesion in aorta. Real-time polymerase chain reaction analysis demonstrated that the fecal abundance of A muciniphila was significantly reduced by Western diet. Replenishment with A muciniphila reversed Western diet–induced exacerbation of atherosclerotic lesion formation without affecting hypercholesterolemia. A muciniphila prevented Western diet–induced inflammation in both the circulation and local atherosclerotic lesion, as evidenced by reduced macrophage infiltration and expression of proinflammatory cytokines and chemokines. These changes were accompanied by a marked attenuation in metabolic endotoxemia. A muciniphila–mediated reduction in circulating endotoxin level could be attributed to the induction of intestinal expression of the tight junction proteins (zona occuldens protein-1 and occludin), thereby reversing Western diet–induced increases in gut permeability. Long-term infusion of endotoxin to Apoe−/− mice reversed the protective effect of A muciniphila against atherosclerosis.
Conclusion—A muciniphila attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier.

2) Bland, Jeffrey. “Intestinal Microbiome, Akkermansia muciniphila, and Medical Nutrition Therapy.” Integrative Medicine: A Clinician’s Journal 15.5 (2016). Intestinal Microbiome, Akkermansia muciniphila, and Medical Nutrition Therapy.

Source: Integrative Medicine: A Clinician’s Journal . Oct2016, Vol. 15 Issue 5, p14-16. 3p. Author(s): Bland, Jeffrey

Abstract:
The gastrointestinal microbiome has become a topic of great interest in medicine in recent years. Genomic sequencing can now be done at a fraction of the cost of a few years ago, and this has allowed for the development and compilation of an extensive amount of data related to the species diversity of the human gastrointestinal microbiome.1 Studies have demonstrated that the intestinal microbiome is sensitive to the composition of the diet.2 It is also recognized that the composition of the microbiome can be altered rapidly in response to dietary changes, stress, chemical exposure, and exercise.3 Both the expanded understanding of the composition of the human microbiome and the ability to measure it through genomic analysis of the stool have resulted in clinicians frequently wanting to know what actionable conclusions can be taken away from an analysis of the gastrointestinal microbiome.

3) pdf
Yamashita, Tomoya, et al. “Gut Microbiota and Coronary Artery Disease.” International Heart Journal 57.6 (2016): 663-671.
Gut microbiota have been attracting increased attention in many fields of medicine recently. We can perform a comprehensive analysis of gut microbiota using next-generation sequencing techniques together with bioinformatics technology, which expands our knowledge of a large ecosystem consisting of a host and gut microbiota. We summarize
some reports about the correlations between gut microbiota and metabolic disorders, particularly atherosclerosis, and discuss future directions for the diagnostic or therapeutic potential of gut microbiota. To take simple examples, we demonstrated that the order Lactobacillales was significantly increased; while the phylum Bacteroidetes was significantly decreased in coronary artery disease (CAD) patients compared with controls or healthy volunteers. The characteristics of
gut microbiota in type 2 diabetes and dyslipidemia have been reported. However, these studies have limitations, and the biological significance of gut microbiota and the causal relationships are still controversial. We hope the reports listed in this review article might lead to the development of a novel therapy to prevent CAD via modulating gut microbiota or their metabolites. (Int Heart J 2016; 57: 663-671)

4)  Brown, J. Mark, and Stanley L. Hazen. “The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases.” Annual review of medicine 66 (2015): 343.

more recently it has begun to be appreciated that low levels of bacteria can actually make it into the bloodstream to cause chronic low grade inflammation systemically (73). The concept that low levels of gut-derived bacteria can appear in the circulation is commonly referred to as “metabolic endotoxemia” because it has been found to be prevalent in many chronic metabolic diseases such as obesity, type II diabetes, and atherosclerosis (73). Although this type of microbe-host signaling cannot be classified as endocrine in nature, it has clear potential to alter CVD risk. In fact, human mutations and mouse knockout studies demonstrate a key role for Toll-like receptor 4 (TLR4) or nucleotide oligomerization domain 2 (NOD2) activation in atherosclerosis development (69–74). Furthermore, microbial activation of these innate immune receptors promotes inflammation that dampens reverse cholesterol transport, while augmenting insulin resistance, hyperlipidemia, and vascular inflammation (76,77) (Figure 1). Collectively, metabolic endotoxemia and engagement of peripheral pattern recognition receptors plays a major role in the pathogenesis of CVD by reorganizing lipid metabolism and promoting inflammatory responses (76,77).

5)  Neves AL, Coelho J, Couto L, et al. Metabolic endotoxemia: a molecular link between obesity and cardiovascular disease. 2013;51:R51–64.
Obesity is associated with significantly increased cardiovascular (CV) risk and mortality. Several molecular mechanisms underlying this association have been implied, among which the intestinal barrier has gained a growing interest. In experimental models of obesity, significant alterations in the intestinal barrier lead to increased intestinal permeability, favoring translocation of microbiome-derived lipopolysaccharide to the bloodstream. This has been shown to result in a two- to threefold increase in its serum concentrations, a threshold named ‘metabolic endotoxemia’ (ME). ME may trigger toll-like receptor 4-mediated inflammatory activation, eliciting a chronic low-grade proinflammatory and pro-oxidative stress status, which may result in high CV risk and target-organ damage. In this review, we discuss the potential molecular implications of ME on several CV risk factors, such as obesity, insulin resistance, dyslipidemia, and oxidative stress, as well as its potential impact on the development of CV target-organ disease.

In order to specifically demonstrate the effect of LPS on the development of atherosclerosis, Lehr et al. showed that LPS-treated animals exhibited significantly accelerated atherosclerosis compared with control animals, using an animal model of hypercholesterolemic rabbits, which received either repeated i.v. injections of endotoxin or a self-limiting cutaneous Staphylococcus aureus infection. Endotoxin-treated animals exhibited significantly accelerated atherosclerosis compared with control animals (Lehr et al. 2001).

In humans, the Bruneck study was the first specifically assessing the impact of subclinical endotoxemia on the development of carotid atherosclerosis. The authors showed that markers of systemic inflammation such as circulating bacterial endotoxin were elevated in patients with chronic infections and were strong predictors of increased atherosclerotic risk (Kiechl et al. 2001).

6)  Lehr, Hans-Anton, et al. “Immunopathogenesis of atherosclerosis Endotoxin accelerates atherosclerosis in rabbits on hypercholesterolemic diet.” Circulation 104.8 (2001): 914-920.
Background— On the basis of our concept that atherosclerosis has an immunopathological background, we tested whether activation of the innate immune system influences its progression.

Methods and Results— Hypercholesterolemic (0.5% wt/wt diet) rabbits received either repeated intravenous injections of endotoxin (Escherichia coli lipopolysaccharide 1.25 to 2.5 μg, once per week) or a self-limiting cutaneous Staphylococcus aureus infection with or without a quinolone antibiotic. Measured laboratory parameters, including LDL and HDL cholesterols, were similar in the different groups of hypercholesterolemic animals. All endotoxin-treated animals developed transient episodes of fever after endotoxin administration. The extent of atherosclerosis was evaluated by computer-assisted morphometry in the aortas en face (Sudan IV) and by histology at 8 weeks after start of the experiments. Endotoxin-treated animals exhibited significantly accelerated atherosclerosis compared with control animals (141±38 versus 45±16 mm3 total lesion volume, n=7 to 9 rabbits each, P<0.001).

Conclusions— Nonspecific stimulation of the innate immune system accelerates cholesterol-induced atherosclerosis. These data support the concept that atherosclerosis has an immunopathological component and render it improbable that a single infectious agent should assume particular importance in its initiation or progression.

7)  Rice, James B., et al. “Low-level endotoxin induces potent inflammatory activation of human blood vessels inhibition by statins.” Arteriosclerosis, thrombosis, and vascular biology 23.9 (2003): 1576-1582.
Background— Low-level endotoxemia (ie, ≥50 pg/mL) in apparently healthy subjects was recently identified as a powerful, independent risk factor for atherosclerosis.

Methods and Results— We treated human saphenous veins (HSVs) with low levels of endotoxin. Release of the proinflammatory chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) was measured by ELISA. Superoxide was determined by using the fluorescent probe dihydroethidium (HE), and monocyte binding was assessed with calcein-labeled U-937 cells. Three- to 4-fold increases in MCP-1 and IL-8 release were observed at endotoxin concentrations of 100 pg/mL; these increases were inhibited by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Studies in cultured endothelial cells suggest that the mechanism is related to inhibition of isoprenylation (ie, geranylgeranylation) rather than cholesterol formation. Endotoxin produced dose-dependent increases in HE fluorescence that were inhibited by the superoxide dismutase mimics Tiron and MnTBAP. Endotoxin potently induced U-937 cell binding to HSV; binding was inhibited by both Tiron and atorvastatin. Toll-like receptor-4 expression was detected in cultured HSV endothelial and smooth muscle cells and in intact HSV.

Conclusions— Clinically relevant levels of endotoxin, as reported in ambulatory populations, have profound inflammatory effects on intact HSV. Inhibition of endotoxin-induced vascular inflammation might contribute to the beneficial effects of statins in treating atherosclerosis.

8)   Stoll, Lynn L., Gerene M. Denning, and Neal L. Weintraub. “Potential role of endotoxin as a proinflammatory mediator of atherosclerosis.” Arteriosclerosis, thrombosis, and vascular biology 24.12 (2004): 2227-2236.
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.
Data from the Bruneck study indicate that blood endotoxin levels in an ambient population of 516 apparently healthy volunteers, with no clinical evidence of infection, ranged from 6 to 209 pg/mL, with a median of 14.3. Individuals with levels of 50 pg/mL or greater were identified to have an increased risk for development of atherosclerosis. Levels of endotoxin in this range induce inflammatory responses in human monocytes and macrophages. In addition, recent data from our laboratory indicate that vascular smooth muscle cells and intact human blood vessels also exhibit profound responsiveness (cytokine release, superoxide production, and monocyte adhesion) to very low levels of endotoxin.28,29 These findings establish the biological plausibility of low level endotoxemia as a mediator of vascular inflammation in atherosclerosis. Moreover, they suggest that in addition to tissue-resident inflammatory cells, vascular smooth muscle cells likely contribute significantly to the inflammation induced by low-level endotoxin in patients who are at risk for atherosclerosis.

9)  Manco, Melania, Lorenza Putignani, and Gian Franco Bottazzo. “Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk.” Endocrine reviews 31.6 (2010): 817-844.
Compelling evidence supports the concepts that gut microbiota actively promotes weight gain and fat accumulation and sustains, indirectly, a condition of low-grade inflammation, thus enhancing the cardiovascular risk. Fewer Bacteroidetes and more Firmicutes seem to characterize the gut microbiota of obese people as compared with that of lean individuals. This difference translates into an increased efficiency of microbiota of obese individuals in harvesting energy from otherwise indigestible carbohydrates. Furthermore, the microbiota also seems able to favor fat accumulation. Indeed, studies performed in germ-free animals have demonstrated that conventionalization of sterile intestine with gut microbiota is associated with an enhanced expression of various lipogenic genes in different tissues, i.e., hepatic, adipose, and muscle tissues. Finally, the microbiota favors systemic exposure to the lipopolysaccharides (LPSs), large glycolipids derived from the outer membrane of Gram-negative bacteria. LPSs can cause a condition of “metabolic endotoxemia” characterized by low-grade inflammation, insulin resistance, and augmented cardiovascular risk. LPSs are a powerful trigger for the innate immune system response. Upon binding to the Toll-like receptor 4 and its coreceptors, LPSs trigger a cascade of responses ultimately resulting in the release of proinflammatory molecules that interfere with modulation of glucose and insulin metabolism, promote development and rupture of the atherosclerotic plaque, and favor progression of fatty liver disease to steatohepatitis. This review gives a comprehensive breakdown of the interaction among gut microbiota, LPSs, and the innate immune system in the development of obesity and promotion of an individual’s cardiovascular risk.
Compelling evidence supports the concepts that gut microbiota directly and indirectly promote weight gain, fat accumulation and sustains a condition of low-grade inflammation, thus enhancing the individual cardiovascular risk. The aim of this review is to provide a comprehensive breakdown of the interaction among microbiota, lipopolysaccharides and the innate immune system in these conditions. This emerging relationship has led to a shift in the interest of researchers studying the pathogenesis of cardiovascular disease from a scenario exclusively involving adipose tissue and muscle, to one in which the main players are immune and non-immune cells from the adipose tissue and the liver. The review also has paid attention to those novel therapeutic approaches which may reduce the impact of the western lifestyle on cardiovascular risk.

10)  Szeto, Cheuk-Chun, et al. “Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients.” Clinical Journal of the American Society of Nephrology 3.2 (2008): 431-436.
Background and objectives: Systemic inflammatory state is a hallmark of peritoneal dialysis (PD) patients, but its etiology remains obscure. Because circulating microbial products are an important cause of systemic immune activation in other conditions such as HIV infection, it was hypothesized that endotoxemia is a cause of systemic inflammatory state and atherosclerosis in PD patients.

Design, setting, participants, & measurements: Plasma lipopolysaccharide (LPS) levels in 30 consecutive new PD patients were measured. The result was compared with serum C-reactive protein (CRP) level, peritoneal transport status, history of pre-existing cardiovascular diseases, and carotid intima media thickness (IMT) by Doppler ultrasound.

Results: Among the 30 PD patients, there were 17 men. The average age was 53.7 ± 15.1 yr. The average endotoxin concentration of PD patients was 0.44 ± 0.18 EU/ml, which was significantly higher than that of patients with chronic kidney disease secondary to Ig-A nephropathy (IgAN) (0.035 ± 0.009 EU/ml, P < 0.0001) and the controls (0.013 ± 0.007 EU/ml, P < 0.0001). In PD patients, plasma LPS concentration had a significant correlation with serum CRP (r = 0.415, P = 0.025) and serum albumin level (r = −0.394, P = 0.034). In contrast, plasma LPS level did not correlate with Charlson’s Comorbidity Index, peritoneal transport characteristics, or nutritional indices. Patients with pre-existing cardiovascular disease (CVD) had higher plasma LPS level than those without CVD (0.53 ± 0.19 versus 0.36 ± 0.16 EU/ml, P = 0.016). Plasma LPS level correlated with carotid IMT (r = 0.438, P = 0.016).

Conclusions: It was found that endotoxemia was probably common in PD patients, and the degree of circulating endotoxemia might be related to the severity of systemic inflammation and features of atherosclerosis. This result suggests that endotoxemia may have a contributory role to the systemic inflammatory state and accelerated atherosclerosis in PD patients.

11)
McIntyre, Christopher W., et al. “Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease.” Clinical Journal of the American Society of Nephrology 6.1 (2011): 133-141.
ackground and objectives Translocated endotoxin derived from intestinal bacteria has a wide range of adverse effects on cardiovascular (CV) structure and function, driving systemic inflammation, atherosclerosis and oxidative stress. This study’s aim was to investigate endotoxemia across the spectrum of chronic kidney disease (CKD).

Design, setting, participants, & measurements Circulating endotoxin was measured in 249 patients comprising CKD stage 3 to 5 and a comparator cohort of hypertensive patients without significant renal impairment. Patients underwent extended CV assessment, including pulse wave velocity and vascular calcification. Hemodialysis (HD) patients also received detailed echocardiographic-based intradialytic assessments. Patients were followed up for 1 year to assess survival.

Results Circulating endotoxemia was most notable in those with the highest CV disease burden (increasing with CKD stage), and a sharp increase was observed after initiation of HD. In HD patients, predialysis endotoxin correlated with dialysis-induced hemodynamic stress (ultrafiltration volume, relative hypotension), myocardial stunning, serum cardiac troponin T, and high-sensitivity C-reactive protein. Endotoxemia was associated with risk of mortality.

Conclusions CKD patients are characteristically exposed to significant endotoxemia. In particular, HD-induced systemic circulatory stress and recurrent regional ischemia may lead to increased endotoxin translocation from the gut. Resultant endotoxemia is associated with systemic inflammation, markers of malnutrition, cardiac injury, and reduced survival. This represents a crucial missing link in understanding the pathophysiology of the grossly elevated CV disease risk in CKD patients, highlighting the potential toxicity of conventional HD and providing a novel set of potential therapeutic strategies to reduce CV mortality in CKD patients.

12) Curr Cardiol Rev. 2016 Sep 1. [Epub ahead of print]
Endotoxin, Toll-like Receptor-4, and Atherosclerotic Heart Disease.
Horseman MA1, Surani S, Bowman JD.
Endotoxin is a lipopolysaccharide (LPS) constituent of the outer membrane of most gram negative bacteria. Ubiquitous in the environment, it has been implicated as a cause or contributing factor in several disparate disorders from sepsis to heatstroke and Type II diabetes mellitus. Starting at birth, the innate immune system develops cellular defense mechanisms against environmental microbes that are in part modulated through a series of receptors known as toll-like receptors. Endotoxin, often referred to as LPS, binds to toll-like receptor 4 (TLR4)/ myeloid differentiation protein 2 (MD2) complexes on various tissues including cells of the innate immune system, smooth muscle and endothelial cells of blood vessels including coronary arteries, and adipose tissue. Entry of LPS into the systemic circulation ultimately leads to intracellular transcription of several inflammatory mediators. The subsequent inflammation has been implicated in the development and progression atherosclerosis and subsequent coronary artery disease and heart failure.
OBJECTIVE:The potential roles of endotoxin and TLR4 are reviewed regarding their role in the pathogenesis of atherosclerotic heart disease.
CONCLUSION:Atherosclerosis is initiated by inflammation in arterial endothelial and subendothelial cells, and inflammatory processes are implicated in its progression to clinical heart disease. Endotoxin and TLR4 play a central role in the inflammatory process, and represent potential targets for therapeutic intervention. Therapy with HMG-CoA inhibitors may reduce the expression of TLR4 on monocytes. Other therapeutic interventions targeting TLR4 expression or function may prove beneficial in atherosclerotic disease prevention and treatment.

13)  Kiechl, Stefan, et al. “Toll-like receptor 4 polymorphisms and atherogenesis.” New England Journal of Medicine 347.3 (2002): 185-192.
In conclusion, the common Asp299Gly TLR4 polymorphism, which attenuates receptor signaling and diminishes the inflammatory response to gram-negative pathogens and, potentially, to other relevant ligands, is associated with low levels of certain circulating mediators of inflammation and a decreased risk of atherosclerosis. These data provide epidemiologic support for the concept that an efficient innate immune defense against bacteria and associated long-term intravascular inflammatory stress are involved in the development of atherosclerosis.

14) Cuaz-Pérolin, Clarisse, et al. “Antiinflammatory and antiatherogenic effects of the NF-κB inhibitor acetyl-11-keto-β-boswellic acid in LPS-challenged ApoE−/− mice.” Arteriosclerosis, thrombosis, and vascular biology 28.2 (2008): 272-277.

Atherosclerotic lesions were induced by weekly LPS injection in apoE−/− mice. LPS alone increased atherosclerotic lesion size by ≈100%, and treatment with AKβBA significantly reduced it by ≈50%. Moreover, the activity of NF-κB was also reduced in the atherosclerotic plaques of LPS-injected apoE−/− mice treated with AKβBA. As a consequence, AKβBA treatment led to a significant downregulation of several NF-κB–dependent genes

15)   Pathobiology. 2005;72(6):325-34.
The antiatherogenic effect of allicin: possible mode of action.
Gonen A1, Harats D, Rabinkov A, Miron T, Mirelman D, Wilchek M, Weiner L, Ulman E, Levkovitz H, Ben-Shushan D, Shaish A.
Author information

Abstract
OBJECTIVE:
Garlic (Allium sativum) has been suggested to affect several cardiovascular risk factors. Its antiatherosclerotic properties are mainly attributed to allicin that is produced upon crushing of the garlic clove. Most previous studies used various garlic preparations in which allicin levels were not well defined. In the present study, we evaluated the effects of pure allicin on atherogenesis in experimental mouse models.
METHODS AND RESULTS:
Daily dietary supplement of allicin, 9 mg/kg body weight, reduced the atherosclerotic plaque area by 68.9 and 56.8% in apolipoprotein E-deficient and low-density lipoprotein (LDL) receptor knockout mice, respectively, as compared with control mice. LDL isolated from allicin-treated groups was more resistant to CuSO(4)-induced oxidation ex vivo than LDL isolated from control mice. Incubation of mouse plasma with (3)H-labeled allicin showed binding of allicin to lipoproteins. By using electron spin resonance, we demonstrated reduced Cu(2+) binding to LDL following allicin treatment. LDL treatment with allicin significantly inhibited both native LDL and oxidized LDL degradation by isolated mouse macrophages.
CONCLUSIONS:
By using a pure allicin preparation, we were able to show that allicin may affect atherosclerosis not only by acting as an antioxidant, but also by other mechanisms, such as lipoprotein modification and inhibition of LDL uptake and degradation by macrophages.

16)   Cardiovasc Res. 2004 Jan 1;61(1):169-76.
Fish oil increases antioxidant enzyme activities in macrophages and reduces atherosclerotic lesions in apoE-knockout mice.
Wang HH1, Hung TM, Wei J, Chiang AN.
The molecular and cellular mechanisms that fish oil (FO) exerts its physiological function are complicated. The present study brings evidence on the in vivo effect of FO on the development of atherosclerosis in apolipoprotein E knockout (apoE(-/-)) mice. We also test the hypothesis that the modulation of the cellular oxidative stress and antioxidant status contributes to the anti-atherosclerotic effect of FO.
METHODS AND RESULTS:
ApoE(-/-) mice were fed a diet rich either in FO or corn oil (CO) for 10 weeks. Both FO and CO had a plasma triacylglycerol-raising effect in apoE(-/-) mice, whereas aortic atherosclerotic lesions were significantly reduced in the mice that had consumed a high FO diet compared to those fed a high CO diet. The levels of hepatic superoxide dismutase (SOD) and catalase (CAT) activities were remarkably higher in the mice fed the FO diet than in mice fed the CO diet and the control diet. We then investigated the effects of FO and CO on the production of superoxide anion (O2*-)) and reactive oxygen species (ROS) in cultured J774 macrophages. Antioxidant status was assessed by the determination of antioxidant enzyme activities. Both FO and CO induced high levels of O2*-) and total ROS at a short time in macrophages. However, only the FO group restored the induction of O2*-) and ROS to near basal levels after oil treatment for 24 h. Throughout the time course experiments, antioxidant enzyme activities in the FO group mostly displayed a greater increase than in the corresponding CO group after the same time period of oil treatment.
CONCLUSIONS:In the present study, FO reduced the formation of atherosclerotic lesions in the aortic arteries of apoE(-/-) mice not through any lipid-lowering effect. The protective role of FO in the development of atherosclerosis may result from its antioxidative defense mechanism through the induction of antioxidant enzyme activities.

17)   Atherosclerosis. 2007 Dec;195(2):e61-8. Epub 2007 Jun 22.
Anti-oxidant and anti-atherogenic properties of liposomal glutathione: studies in vitro, and in the atherosclerotic apolipoprotein E-deficient mice.
Rosenblat M1, Volkova N, Coleman R, Aviram M.
1The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa 31096, Israel.
Abstract Liposomal glutathione, but not the control liposomes (with no glutathione), dose-dependently inhibited copper ion-induced low density lipoprotein (LDL) and HDL oxidation. As peroxidase activity was found to be present in both LDL and HDL, it has contributed to the anti-oxidative effects of liposomal glutathione. In-vitro, no significant effect of liposomal glutathione on J774 A.1 macrophage cell-line oxidative stress and on cellular cholesterol metabolism was observed. In contrast, in the atherosclerotic apolipoprotein E-deficient (E(0)) mice, consumption of liposomal glutathione (12.5 or 50mg/kg/day, for 2 months), but not control liposomes, resulted in a significant reduction in the serum susceptibility to AAPH-induced oxidation by 33%. Liposomal glutathione (50mg/kg/day) consumption also resulted in an increment (by 12%) in the mice peritoneal macrophages (MPM) glutathione content, paralleled by a significant reduction in total cellular lipid peroxides content (by 40%), compared to placebo-treated mice MPM. MPM paraoxonase 2 activity was significantly increased by 27% and by 121%, after liposomal glutathione consumption (12.5 or 50mg/kg/day, respectively). Analyses of cellular cholesterol fluxes revealed that, liposomal glutathione (12.5mg/kg/day) consumption, decreased the extent of oxidized-LDL (Ox-LDL) uptake by 17% and the cellular cholesterol biosynthesis rate, by 34%, and stimulated HDL-induced macrophage cholesterol efflux, by 19%. Most important, a significant reduction in macrophage cholesterol mass (by 24%), and in the atherosclerotic lesion area (by 30%) was noted. We thus conclude that liposomal glutathione possesses anti-oxidative and anti-atherogenic properties towards lipoproteins and macrophages, leading to attenuation of atherosclerosis development.

18)   J Agric Food Chem. 2008 Dec 10;56(23):11485-92. doi: 10.1021/jf801876n.
Anthocyanins from purple sweet potato Ipomoea batatas cultivar Ayamurasaki suppress the development of atherosclerotic lesions and both enhancements of oxidative stress and soluble vascular cell adhesion molecule-1 in apolipoprotein E-deficient mice.
Miyazaki K1, Makino K, Iwadate E, Deguchi Y, Ishikawa F.
1Yakult Central Institute for Microbiological Research, Tokyo. Japan.
Abstract
We evaluated the protective potential of anthocyanins from purple sweet potato Ipomoea batatas cultivar Ayamurasaki (APSP) against low-density lipoprotein (LDL) oxidation in vitro and atherosclerotic lesion development in apolipoprotein E-deficient mice given a cholesterol- and fat-enriched diet with or without 1% APSP for 4 weeks. APSP protected LDL against oxidation more potently than other anthocyanins and l-ascorbic acid in vitro. In mice, APSP significantly lowered the atherosclerotic plaque area to about half of the control, the liver level of thiobarbituric acid-reactive substances as an oxidative stress marker, and the plasma level of soluble vascular cell adhesion molecule-1 (sVCAM-1). However, APSP showed no effects on body weight and cholesterol and lipid levels in the plasma. The results suggest that APSP can suppress the development of atherosclerotic lesions and both enhancements of oxidative stress and sVCAM-1 independently of the changes in cholesterol and lipid levels in mice.

19)   J Agric Food Chem. 2009 Dec 9;57(23):11106-11. doi: 10.1021/jf9035468.
Atheroprotective effects of bilberry extracts in apo E-deficient mice.
Mauray A1, Milenkovic D, Besson C, Caccia N, Morand C, Michel F, Mazur A, Scalbert A, Felgines C.
1INRA, Unité de Nutrition Humaine, UMR1019, Centre de Recherche de Clermont Ferrand/Theix, Saint Genès Champanelle, France.
Abstract
Previous studies have demonstrated that the intake of berry foods was associated with a reduced risk of cardiovascular diseases. The aim of the present study was to evaluate the effects of two bilberry extracts, one rich in anthocyanins extracted from untreated bilberries (BE) and a second one extracted from yeast-fermented bilberries (FBE), on the development of atherosclerosis in apolipoprotein E-deficient mice (apo E(-/-)). Apo E(-/-) mice received for 16 weeks a diet supplemented with 0.02% of either BE or FBE. Atherosclerotic plaque area was measured in the aortic sinus. Supplementation of the diet with both bilberry extracts led to a significant inhibition of plaque development, whereas no effect on oxidative stress parameters or lipid profiles could be observed, suggesting the implication of other mechanisms of action. In addition, a better protection was observed with FBE, suggesting that the fermentation generates new bioactive compounds more effective in attenuating progression of the atherosclerotic lesions.

20)  J Nutr. 2001 Oct;131(10):2606-18.
Novel tocotrienols of rice bran inhibit atherosclerotic lesions in C57BL/6 ApoE-deficient mice. Qureshi AA1, Salser WA, Parmar R, Emeson EE.
Author information  1Advanced Medical Research, Madison, WI 53719, USA.
Abstract
We are studying novel tocotrienols, which have a number of activities that might interfere with the formation of atherosclerotic plaques, including hypocholesterolemic, antioxidant, anti-inflammatory and antiproliferation effects. This study compared the effects of alpha-tocopherol, the tocotrienol-rich fraction (TRF(25)) and didesmethyl tocotrienol (d-P(25)-T3) of rice bran on the pathogenesis of atherosclerotic lesions in C57BL/6 apolipoprotein (apo)E-deficient (-/-) mice. These mice are an excellent model because they become hyperlipidemic even when they consume a low fat diet and they develop complex atherosclerotic lesions similar to those of humans. These compounds were also tested in wild-type C57BL/6 apoE (+/+) and (+/-) mice fed low or high fat diets. When a high fat diet was supplemented with alpha-tocopherol, TRF(25) or d-P(25)-T3 and fed to mice (+/+) for 24 wk, atherosclerotic lesion size was reduced 23% (P = 0.33), 36% (P = 0.14) and 57% (P < 0.02), respectively, and in mice (+/-) fed for 18 wk, lesions were reduced by 19% (P = 0.15), 28% (P < 0.01) and 33% (P < 0.005), respectively, compared with mice fed a control diet. A low fat diet did not cause atherosclerotic lesions in these mice. The low fat diet supplemented with TRF(25) or d-P(25)-T3 fed to apoE-deficient (-/-) mice for 14 wk decreased atherosclerotic lesion size by 42% (P < 0.04) and 47% (P < 0.01), respectively, whereas alpha-tocopherol supplementation resulted in only an 11% (P = 0.62) reduction. These results demonstrate the superior efficacy of tocotrienols compared with alpha-tocopherol. Although tocotrienols decreased serum triglycerides, total and LDL cholesterol levels, the decreases in atherosclerotic lesions seem to be due to the other activities. Serum tocol concentrations in various groups are also described. This is the first report of a significant reduction in the atherosclerotic lesion size in all three genotypes of apoE mice fed a novel tocotrienol (d-P(25)-T3) of rice bran. Dietary tocotrienol supplements may provide a unique approach to promoting cardiovascular health.

21)   Ni, Mei, et al. “Atherosclerotic plaque disruption induced by stress and lipopolysaccharide in apolipoprotein E knockout mice.” American Journal of Physiology-Heart and Circulatory Physiology 296.5 (2009): H1598-H1606.

22)   Kim, S. J., et al. “The Protective Effect of Apamin on LPS/Fat-Induced Atherosclerotic Mice.” Evidence-based complementary and alternative medicine: eCAM 2012 (2011): 305454-305454.
Apamin, a peptide component of bee venom (BV), has anti-inflammatory properties. However, the molecular mechanisms by which apamin prevents atherosclerosis are not fully understood. We examined the effect of apamin on atherosclerotic mice. Atherosclerotic mice received intraperitoneal (ip) injections of lipopolysaccharide (LPS, 2 mg/kg) to induce atherosclerotic change and were fed an atherogenic diet for 12 weeks. Apamin (0.05 mg/kg) was administered by ip injection. LPS-induced THP-1-derived macrophage inflammation treated with apamin reduced expression of tumor necrosis factor (TNF)-α, vascular cell adhesion molecule (VCAM)-1, and intracellular cell adhesion molecule (ICAM)-1, as well as the nuclear factor kappa B (NF-κB) signaling pathway. Apamin decreased the formation of atherosclerotic lesions as assessed by hematoxylin and elastic staining. Treatment with apamin reduced lipids, Ca2+ levels, and TNF-α in the serum from atherosclerotic mice. Further, apamin significantly attenuated expression of VCAM-1, ICAM-1, TGF-β1, and fibronectin in the descending aorta from atherosclerotic mice. These results indicate that apamin plays an important role in monocyte/macrophage inflammatory processing and may be of potential value for preventing atherosclerosis.

23)   Chistiakov, Dmitry A., et al. “Role of gut microbiota in the modulation of atherosclerosis-associated immune response.” Frontiers in microbiology 6 (2015).

24)  Ostos, Maria A., et al. “Implication of natural killer t cells in atherosclerosis development during a LPS‐induced chronic inflammation.” FEBS letters 519.1-3 (2002): 23-29.
Atherosclerosis has many features of a chronic inflammatory disease. To evaluate the role of lipopolysaccharide (LPS), mimicking a systemic infection, we administered the endotoxin to apolipoprotein E (apoE)-deficient mice. LPS injections increase the atherosclerotic lesion size and the titer of plasma autoantibodies directed against oxidized low-density lipoprotein. We found that Th1 and Th2 T cells help the activation of B cells in the autoimmune response. The number of interleukin-4 producing natural killer T cells is highly increased in peripheral blood, liver, spleen and thymus cells, as well as in the atherosclerotic plaque of the LPS-treated mice. Finally, an important adventitial infiltrate of activated lymphocytes, sign of an advanced atherosclerosis, is observed only in the LPS-treated mice. Our results demonstrate that LPS administration aggravates atherosclerosis in apoE-deficient mice. LPS-injected apoE-deficient mice appear to be an excellent animal model to analyze the implementation of new therapeutic approaches in the treatment of atherosclerosis by manipulating immunological effectors.

25)  Babaev, Vladimir R., et al. “Combined Vitamin C and Vitamin E Deficiency Worsens Early Atherosclerosis in ApoE-Deficient Mice.” Arteriosclerosis, thrombosis, and vascular biology 30.9 (2010): 1751.
Atherosclerosis is an inflammatory condition associated with oxidative stress, but controversy persists regarding whether antioxidants such as vitamins C and E are preventative. To assess the role of combined deficiencies of vitamins C and E on the earliest stages of atherosclerosis, four combinations of vitamin supplementation (Low C/Low E, Low C/High E, High C/Low E, High C/High E) were studied in atherosclerosis-prone apolipoprotein E (apoE)-deficient mice also unable to synthesize their own vitamin C (gulo−/−). The effect of a more severe depletion of vitamin C alone was evaluated in a second experiment using gulo−/− mice carrying the hemizygous deletion of SVCT2, the vitamin C transporter.
After 8 weeks on a high-fat diet (16% lard, 0.2% cholesterol), atherosclerosis developed in the aortic sinus areas of mice in all diet groups. Each vitamin-deficient diet significantly decreased liver and brain contents of the corresponding vitamin. Combined deficiency of both vitamins increased lipid peroxidation, doubled plaque size, and increased plaque macrophage content by 2-3-fold in males, although only plaque macrophage content was increased in females. A more severe deficiency of vitamin C in gulo−/− mice with defective cellular uptake of vitamin C increased both oxidative stress and atherosclerosis in apoE−/− mice compared to littermates on a diet replete in vitamin C, again most clearly in males.  Combined vitamin E and C deficiencies are required to worsen early atherosclerosis in an apoE-deficient mouse model. However, a more severe cellular deficiency of vitamin C alone promotes atherosclerosis when vitamin E is replete.

26) Glaros, Trevor G., et al. “Causes and consequences of low grade endotoxemia and inflammatory diseases.” Front Biosci (Schol Ed) 5 (2013): 754-765. Causes consequences of low grade endotoxemia Glaros Trevor Front Biosci 2013

27) Houser, Madelyn C., and Malú G. Tansey. “The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis?.” npj Parkinson’s Disease 3.1 (2017): 3.
A number of reports now indicate that PD patients have increased intestinal permeability compared to healthy controls

Thyroid protective of endotoxemia

Cholesterol protective of endotoxemia

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