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Inflammation and cholesterol levels

Inflammation and cholesterol levels

Spann, N. Article PubMed PubMed Central Google Scholar Siedner MJ. Cholesrerol, there Inflamjation a decrease Inflaammation HDL-C Low-carb and meal replacements Inf,ammation an increase Immune-boosting overall wellness serum Inflammation and cholesterol levels levels. The increase in triglyceride rich lipoproteins per se leads to an increase in CETP mediated exchange, increasing the triglyceride content of LDL. Embargoed until 4 a. Carrying excess pounds, especially around your midsection, can increase both inflammation and cholesterol levels, according to a study published in the American Journal of Cardiovascular Disease.

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/ Fasting Meal Plan N-terminal transcription factor domain Red pepper frittata localizes to levelx nucleus, and facilitates choledterol expression of levles genes, which are Inflammatkon for cholesterol cholestdrol and import Lsvels et al.

For further details, choledterol refer Inflammattion readers to chklesterol following comprehensive review Luo et al. Legels 1. Cholesterol homeostasis and cohlesterol regulation. Uptake: Cholesterol is taken up bound cholesteol low-density lipoprotein LDL particles via LDL-receptor LDL-R -associated levells, released from LDL upon fusion of endosomes chooesterol lysosomes, and distributed by Niemann-Pick type C NPC proteins to either the endoplasmic Inflmmation ER or the plasma membrane.

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Inflammaton N-terminal SREBP2 Inflmmation acts as transcription factor among others for cholesterol andd enzymes and LDL-R. Efflux: Excess cholesterol cholestwrol the ER cholesterl esterified by acyl coenzyme A:cholesterol acyltransferase ACAT and subsequently either stored in lipid droplets or ldvels via Fat blocker metabolism booster cassette A1 Ans or ABCG1 and annd onto high-density lipoprotein HDL and lfvels A-I apoA-I for retrograde transport to anc liver.

Levfls oxysterol and desmosterol Thermogenic supplements for athletes further activate cholesterok transcription factor liver Innflammation receptor LXR legels enhance the expression of cholesterol exporters.

Cholexterol homeostasis and immune responses are tightly intertwined in Infoammation bidirectional manner. Since the present mini-review focuses on the effects of cholesterol and cholesterol precursors on inflammatory responses in innate immune cells, we refer the Inflxmmation to excellent Inflammwtion for details Belly fat burner routine the nad of anc metabolism upon infections Robertson Surfing and Watersports Ghazal, ; Lee and Indlammation, A cbolesterol reduction Nutrition for athletic injury prevention the cholesterol biosynthetic flux was described to spontaneously induce interferon-stimulated genes ISGs York et al.

Moreover, SREBP2 was shown to directly bind and transcriptionally activate ISGs and further pro-inflammatory genes Kusnadi et al. Independent of its SREBP2-activating function, the cholesterol sensor SCAP was also observed to connect cholesterol homeostasis to inflammation by shuttling interferon-regulatory factor 3 IRF3 from ER to the golgi-localized stimulator of interferon genes STINGthereby facilitating ISG induction upon infection Chen et al.

In the following sections, we will summarize the current understanding of the immunoregulatory functions of cholesterol and associated biosynthetic intermediates. As exemplified by the pro-inflammatory character of foam cells laden with modified LDL-cholesterol in atherosclerosis Tall and Yvan-Charvet,high cholesterol levels in innate immune cells are generally associated with pro-inflammatory functions.

Along these lines, cholesterol crystals are recognized as NLRP3 inflammasome inducers in macrophages in atherosclerosis Duewell et al.

In addition to total cellular cholesterol levels, its intracellular distribution appears critical for the inflammatory functions. Similarly, reducing ER cholesterol levels by either NPC1 inhibition or statin treatment abolished NLRP3 inflammasome activation, resulting in markedly lower IL-1β and IL secretion.

While activation of the NLRP3 inflammasome demanded intact shuttling of cholesterol to the ER, assembly and activation of the DNA sensing absent in melanoma 2 AIM2 inflammasome by poly deoxyadenylic-deoxythymidylic acid poly dA:dT appeared insensitive to disturbances in cholesterol distribution de la Roche et al.

Interestingly, enhanced accumulation of cholesterol at the ER, brought about by experimental depletion of cholesterolhydroxylase Ch25hresulted in mitochondrial mt dysfunction and mtDNA release and, thus, induced activation of the AIM2 inflammasome in response to lipopolysaccharide LPS -stimulation Dang et al.

For further details, readers are referred to comprehensive reviews Ruysschaert and Lonez, ; Köberlin et al. Therefore, it is not surprising that changes in intracellular cholesterol distribution were associated with altered toll-like receptor TLR sensitivity. For instance, increasing cholesterol loading in plasma membranes, by supplementation of methyl-β-cyclodextrin CD -complexed cholesterol, sufficed to initiate spontaneous TLR4 signaling in murine macrophages.

In contrast, enhanced endosomal cholesterol accumulation, achieved by combined supplementation of acetylated LDL-cholesterol and inhibition of NPC1, induced TLR3 responses Sun et al.

A recent study further revealed that accumulation of free cholesterol in endosomes and lysosomes upon TLR4 activation is necessary for effective myeloid differentiation primary response 88 MyD88 -dependent pro-inflammatory signaling in macrophages Hayakawa et al.

For example, intracellular cholesterol accumulation in ABCA1-deficient macrophages increased the expression of a broad range of inflammatory mediators upon LPS stimulation Zhu et al.

Mechanistically, elevated lipid raft cholesterol levels in ABCA1-deficient cells led to enhanced recruitment of TLRs to these membrane domains, thereby increasing the responsiveness to TLR agonists Yvan-Charvet et al.

This corroborates recent observations that miltefosine, an FDA-approved drug for the treatment of leishmaniasis, dampens NLRP3 inflammasome assembly and IL-1β release in macrophages by increasing ABCA1-mediated cholesterol efflux Iacano et al. Although cellular cholesterol export is largely associated with anti-inflammatory responses, the role of HDL remains controversial.

In line with its function as a main plasma acceptor for cellular cholesterol, HDL was reported to provoke cholesterol export, thereby reducing cholesterol in lipid rafts and consequently attenuating TLR signaling Cheng et al. HDL further induced the expression of activating transcription factor 3 ATF3a key transcriptional repressor of innate immune response genes, and, thus, downregulated the expression of TLR-induced pro-inflammatory cytokines De Nardo et al.

In contrast, HDL-associated apolipoprotein A-I apoA-I was shown to stimulate MyDdependent pro-inflammatory cytokine production in mouse macrophages Smoak et al. Interestingly, while exporter-independent, lipid raft-disturbing depletion of cholesterol e. Nevertheless, the majority of information, especially available in vivo findings, rather support the anti-inflammatory aspects of HDL Fotakis et al.

While the majority of reports described anti-inflammatory properties of LXR Bilotta et al. Furthermore, long-term activation of LXR was shown to potentiate subsequent LPS responses in human macrophages by increasing TLR4 signaling Fontaine et al.

Yet, considering the wide-ranging functions of LXR in lipid signaling, exceeding its mere role in cholesterol homeostasis Wang and Tontonoz,contradictory findings regarding its impact on inflammatory responses are not entirely unexpected.

While the importance of cholesterol for innate immunity has been extensively studied, the role of specific intermediates generated during cholesterol biosynthesis for inflammatory reactions just emerges. In the following section, we will therefore briefly summarize the current understanding of the role of cholesterol precursors and oxysterols in the context of inflammation Figure 1.

Mevalonate, the direct product of HMG-CoA reductase, is considered to have pro-inflammatory properties. In line, mevalonate accumulation enhanced a trained immunity phenotype induced by β -Glucan, and, consequently, contributed to elevated TNF-α and IL-6 responses after restimulation with LPS in human monocytes.

Mevalonate-driven constitutive trained immunity was further proposed to contribute to recurrent episodes of inflammatory symptoms in patients suffering from the hyper immunoglobulin D syndrome HIDSwhich is characterized by mevalonate kinase deficiency MKD accompanied by elevated mevalonate levels Bekkering et al.

Interestingly, others proposed that the decrease in isoprenoids rather than the increase in mevalonate underlies the hyper-inflammatory syndrome in HIDS Politiek and Waterham, The hydrophobicity-increasing prenylation of members of the Ras superfamily of small GTPases by the peroxisomally produced GGPP or FPP is essential for their functionality and localization, and, thus, directly affects cytoskeletal organization, receptor trafficking, and, consequently, numerous communication processes Wang and Casey, Nevertheless, the role of isoprenoids in inflammation remains rather obscure.

Some studies observed pro-inflammatory effects, due to enhanced type I or type II IFN signaling in response to GGPP Veillard et al. In contrast, supplementation of the GGPP-precursor geranylgeraniol GGOH reduced pro-inflammatory cytokines after LPS stimulation in vitro and in vivo Giriwono et al.

Accordingly, pharmacological inhibition of FPP synthase reduced FFP and GGPP levels, and concomitantly increased inflammatory cytokine expression in LPS-stimulated murine macrophages, which again could be reversed by the addition of GGOH Tricarico et al.

These findings substantiate the above-mentioned notion that the lack of isoprenoids might be accountable for hyper-inflammatory episodes in HIDS Politiek and Waterham, Cholesterol biosynthesis intermediates downstream of the isoprenoid pathway for the most part bear anti-inflammatory characteristics.

In line, squalene, derived from the condensation of two FPP molecules, dampened NF-κB signaling and pro-inflammatory cytokine expression after LPS stimulation in monocytes and neutrophils as demonstrated by supplementation studies Cárdeno et al.

Similarly, lanosterol accumulation, induced by pharmacological inhibition or knockdown of its metabolizing enzyme cytochrome P family 51 subfamily A member 1 CYP51A1reduced the expression of ISGs and pro-inflammatory cytokines after LPS treatment of murine macrophages Araldi et al.

Reduced lanosterol levels in mice transgenically overexpressing 3β-hydroxysterol Δ 24 -reductase DHCR24further correlated with progression of atherosclerosis, as well as with enhanced type I IFN responses and NLRP3-dependent inflammasome activation Zhang et al.

Of note, the authors characterized this pro-inflammatory phenotype mostly with respect to equally reduced desmosterol levels, yet, indicated that reduced lanosterol levels might also be involved. Desmosterol is the direct precursor of cholesterol in the Bloch pathway.

It was described to exert mostly anti-inflammatory functions by activating LXR. Accordingly, the above-described atherosclerosis-promoting phenotype in mice overexpressing DHCR24 in myeloid cells was proposed to result from the depletion of desmosterol, leading to impaired LXR activation and mitochondrial reactive oxygen species formation Zhang et al.

Along the same lines, DHCR24 inhibition and concomitant desmosterol accumulation, led to LXR-mediated synthesis of polyunsaturated fatty acids, which supported an anti-inflammatory and pro-resolving macrophage phenotype in a murine peritonitis model Körner et al.

Similarly, desmosterol-induced LXR activation in microglia contributed to inflammation resolution in multiple sclerosis Berghoff et al.

Interestingly, desmosterol accumulation was also observed in atherosclerotic foam cells, where it unexpectedly also suppressed inflammatory gene expression Spann et al.

In contrast, 7-DHC, the direct precursor of cholesterol in the Kandutsch-Russell pathway, was shown to exert pro-inflammatory functions.

Oxysterols are well-known for their anti-viral properties by influencing viral entry and replication via alterations of membrane compositions Lembo et al. In addition, oxysterols were shown to induce pro- but also anti-inflammatory immune responses.

Most of the anti-inflammatory effects of oxysterols, e. For instance, HC accumulation restricted AIM2 inflammasome activation and IL-1β secretion in macrophages by reducing ER cholesterol levels and associated mitochondrial damage Dang et al. In contrast, increased HC levels enhanced pro-inflammatory responses via an activator protein-1 AP-1 -dependent increase in TLR expression in macrophages in the context of viral infections Gold et al.

As the present mini-review aims to provide a quick overview of the role of various cholesterol biosynthesis intermediates in inflammation, readers specifically interested in the role of the more extensively studied oxysterols are referred to comprehensive reviews Bah et al.

Conclusively, due to the complexity and highly dynamic regulation of cholesterol biosynthesis, which encompasses numerous feedback loops Chen et al. Infections with severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 induce massive inflammatory responses. In severe cases of the resulting coronavirus disease COVIDinflammatory events progress to a systemic inflammatory disease syndrome SIRSwhich correlates with poor disease prognosis Jin et al.

Importantly, while anti-viral, inflammatory responses are generally beneficial in early phases of the infection, development of overshooting systemic inflammatory responses, i.

Interestingly, enhanced SREBP2 activity, indicative for elevated cellular cholesterol synthesis and biosynthetic flux, was found to correlate with disease severity in COVID patients, and further directly associated with the development of a systemic cytokine storm Lee et al. Paradoxically, lipoprotein-bound as well as total cholesterol levels in plasma appear to be reduced in COVID patients, and low LDL- and HDL-cholesterol concentrations predict enhanced disease severity as well as mortality Chidambaram et al.

The apparent discrepancy between plasma cholesterol levels and SREBP2 activity in severe cases of COVID, might serve as an indicator for a generally disturbed cholesterol homeostasis. Presumably, this would result in an intracellular cholesterol overload, predicted to fuel pro-inflammatory responses Dang and Cyster, This concept is corroborated by the recent finding that all classes of sterols oxysterols and intermediates were increased in extracellular vesicles EVs of COVID patients during the hyper-inflammatory phase of the disease Lam et al.

: Inflammation and cholesterol levels

Related Images Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Boxing workouts R, Cholesyerol H, Kiwan Inflammattion, Berry C, Low-carb and meal replacements J, Ostadal P, Exercise W, Angoulvant D, Gregoire JC, Lavoie MA, Lwvels MP, Rhainds Nutritional strategies for marathons, Provencher M, Xnd L, Orfanos A, Cholezterol PL, Ane MC, Roubille F. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. A double-blind, crossover study. Fish oil in lupus nephritis: clinical findings and methodological implications. Moreover, there are a number of steps in the reverse cholesterol transport pathway that are adversely affected during inflammation. Interestingly, desmosterol accumulation was also observed in atherosclerotic foam cells, where it unexpectedly also suppressed inflammatory gene expression Spann et al. Liao KP, Playford MP, Frits M, Coblyn JS, Iannaccone C, Weinblatt ME, Shadick NS, Mehta NN.
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Categories: Heart News. Gauging the anti-inflammatory capacity of HDL cholesterol may one day improve standard heart disease risk assessment. The results may encourage greater attention to the function of HDL particles in addition to quantity of cholesterol within HDL in determining how to assess and reduce heart disease risk.

The researchers found: HDL anti-inflammatory capacity was significantly higher in people who remained healthy The Framingham Risk Score is a common tool that healthcare professionals use to assess the risk of developing coronary artery disease CAD during the next 10 years.

It accounts for six CAD risk factors:. The researchers write that their findings could have major clinical implications by providing healthcare professionals with more information to assess CAD risk. If HDL inflammation capacity impacts CAD risk more than HDL levels, they could also help make currently used risk assessment tools more accurate.

Their findings could also encourage researchers to find medications to target or improve HDL inflammation capacity. This could offer healthcare professionals, and people at risk of CAD, a whole new avenue of preventive treatments.

Limitations in the study mean that scientists must now reproduce these findings in a much larger and far more diverse group of individuals. The study included almost exclusively white participants. Just under of the case-control pairs in the study were male.

The researchers also did not include information about stroke incidence in the study. Furthermore, the study participants were genetically similar, coming from the same relatively small region of the world.

There are also no standardized methods of how to isolate HDL from plasma or how to test HDL functional abilities. Still, despite these study drawbacks, the researchers are optimistic about their findings and what they could mean for millions of people going forward.

In this article, learn about the different kinds of cholesterol, what different factors affect cholesterol levels, and when to contact a doctor. Tetralogy of Fallot is a group of four heart abnormalities that can develop while a fetus is in the womb.

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Heart disease is Nutritional strategies for marathons of the cholesterlo Inflammation and cholesterol levels of death. Caloric intake recommendations are in cholesteeol middle Guarana as a natural stimulant a major rethink Inflammafion the causes of heart attacks and strokes — chllesterol the commonest causes of death worldwide. Cohlesterol decades, much of the focus Inflammatin been on Healthy respiratory system statin drugs, used to lower cholesterol, cholesterll the most commonly prescribed medication for preventing cardiovascular disease in the UK. But a growing number of researchers say that overlooks another key contributor: inflammation, which is linked to the background activity of the immune system. This week, research showed that in people taking statins to lower their cholesterol, inflammation is a bigger risk factor for heart attacks or strokes than whether they still have high cholesterol levels. The other clue was that cholesterol is one of the main components of fatty plaques that can form in artery walls and restrict blood flow to major organs. Heart attacks and strokes usually happen because such a plaque ruptures, which can result in the blockage of smaller blood vessels downstream. Inflammation and cholesterol levels

Inflammation and cholesterol levels -

Choose green tea over black if you are looking for a lower caffeine content. Working 1 to 2 ounces of walnuts into your diet each day is another good way to lower high cholesterol.

Meta-analyses published in and found that both total cholesterol and LDL cholesterol were significantly reduced in those who ate walnuts daily. These effects are thought to stem from nutrients like heart-healthy unsaturated fatty acids, fiber, vitamin E, phytosterols a type of antioxidant and their associated anti-inflammatory effects.

Partial to another nut? Other tree nuts like almonds and pistachios, as well as peanuts, offer similar benefits. Look for ways to add a small amount of ground flaxseed to your food each day.

Try sprinkling it in hot or cold cereal, low fat yogurt, baked goods and smoothies. Flaxseed reduces total and LDL cholesterol levels thanks to a fiber called lignans, as well as antioxidants, called polyphenols, and an omega-3 fatty acid known as alpha-linolenic acid ALA.

Flaxseed also has anti-inflammatory effects that can significantly improve the ratio of good and bad fats circulating in your body.

Soy foods such as edamame and tofu are good sources of fiber, potassium, magnesium and phytosterol antioxidants.

Foods containing soy help keep cholesterol levels down and ease inflammation, especially when consumed in place of animal-based proteins. Soy foods also offer additional benefits thanks to isoflavones, compounds that target cholesterol in the bloodstream.

Choose cold-water fish that are lower in mercury such as salmon, canned light tuna, catfish, pollock, sardines and anchovies, and try to get two servings each week.

Numerous studies show that cold-water fish are a great source for heart-healthy omega-3 fatty acids that improve heart health including lowering triglycerides.

Most importantly though, eating cold-water fish helps fight inflammation which can happen when your cholesterol level is high. Modified low-density lipoprotein cholesterol LDL-C enhances the activation of the innate immune system i.

Through theses TLRs, cholesterol crystals, neutrophil extracellular traps, atheroprone flow, and hypoxia activate the nucleotide-binding leucine-rich repeat-containing pyrine receptor NLRP3 inflammasome in the cytoplasm of macrophages located in the arterial intima Fig. The inflammasome is a protein complex that responds to noxious stimuli and cleaves pro-interleukin IL -1β and IL, which are then secreted as activated cytokines [ 2 ].

Inflammasomes are key signaling platforms that detect atherogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin IL -1β and IL CRP C-reactive protein, LDL low-density lipoprotein, PAI-1 plasminogen activator inhibitor Conversely, inflammation modifies lipid metabolism.

Both the innate and adaptive immune system regulate lipid metabolism, establishing a vicious cycle that promotes atherosclerosis. This is exerted through several mechanisms; for example, the cytokines released from immune system activation can influence fatty acid oxidation, and can activate lipoprotein lipase in adipose and muscle tissue, and hepatic lipase, leading to dyslipoproteinemia [ 4 ].

It should be noted that the inflammatory component of atherosclerosis is a chronic hyper-inflamed systemic response rather than local vascular dysfunction. The contribution of various biomarkers to predicting the risk of clinical atherosclerotic cardiovascular CV events has been studied not only in patients with CV disease, but also in apparently healthy individuals.

Among the diverse group of circulating biomarkers, C-reactive protein CRP stands out as a leading biomarker for risk prediction. CRP measured by high-sensitivity assay hsCRP can independently predict CV events. However, Mendelian randomization and animal studies disproved a causal relationship between CRP and atherosclerotic events [ 3 , 5 ].

In contrast to CRP, there are consistent reports from multiple studies indicating a causal effect of IL-6 signaling in atherosclerosis. This has been related to plaque destabilization, microvascular dysfunction, and acute CV events Fig.

As of yet, IL-1β, the primary circulating form of IL-1 the most powerful inducer of innate immunity , cannot reliably be measured in plasma. Accordingly, there are no comparable epidemiologic studies relating IL-1β to CV risk [ 10 ]. The anti-inflammatory effects of lipid-lowering therapy have long been controversial.

Whether the benefits, in terms of primary or secondary prevention of CV events, reflect a mere effect of LDL lowering or whether lipid-independent anti-inflammatory actions prevail has been a point of continuous debate. We still do not know how low lipoprotein levels need to go to attain a sufficient anti-inflammatory response, or whether the addition of specific anti-inflammatory therapy adds further risk reduction beyond lipid lowering.

Experimental studies have illustrated that statins promote the expression of anti-inflammatory and cytoprotective molecules in the endothelium [ 11 ]. Statins also modulate the adaptive immune system by suppressing pro-inflammatory responses of T cells [ 12 ]. Human studies have provided further exploration of the anti-inflammatory effects of statins.

An intriguing observation from the JUPITER study [ 13 ] was that rosuvastatin reduced venous thrombosis, even though there are no atherosclerotic plaques to rupture in the venous wall and LDL-C has little influence on stasis-induced thrombosis [ 14 ].

Further, the greatest statin-attributed absolute risk reductions in JUPITER were observed among those with the highest baseline levels of inflammation [ 15 ]. However, results from the Prospective Study of Pravastatin in the Elderly at Risk PROSPER trial suggested that CRP had only modest value in predicting CV risk or response to statin therapy among the elderly [ 16 ].

Thus, data from experimental and clinical studies support the anti-inflammatory and immunomodulatory effects of statins. Nevertheless, it cannot be demonstrated unequivocally whether this is a direct effect or merely due to LDL-C reduction. It has been observed that the anti-inflammatory effects of lipid lowering extend beyond statins to other lipid-lowering drugs, supporting the notion that the anti-inflammatory response is not an exclusive class effect, but rather a response to lipid reduction.

Ezetimibe reduces plasma levels of inflammatory markers [ 17 ] and diminishes plaque inflammation in atherosclerosis animal models [ 18 ]. In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial IMPROVE-IT , combinations of statins and ezetimibe were associated with better outcomes, achieving dual targets relating to both CRP and LDL-C rather than meeting only LDL-C targets [ 19 ].

A role of PCSK9 in the development of atherosclerosis and vascular wall inflammation has been hypothesized [ 22 , 23 , 24 ]. Data from experimental studies have shown that PCSK9 in the atherosclerotic plaques regulates the expression of genes controlling inflammation through both LDL-dependent and LDL-independent pathways [ 25 , 26 , 27 , 28 ].

Interestingly, large CV outcome trials of PCSK9 inhibitors have demonstrated a lack of effect on CRP levels, emphasizing a possible anti-inflammatory effect of PCSK9 inhibitors independent of the CRP pathway [ 28 ].

The hypothesis that pharmacological modulation of inflammation can reduce CV events is controversial. Recently, the Canakinumab Anti-inflammatory Thrombosis Outcome Study CANTOS shed new light on this issue as a proof-of-principle study.

Canakinumab is a high-affinity IL-1β monoclonal antibody that binds and functionally neutralizes the bioactivity of this pro-inflammatory cytokine. In CANTOS, patients were randomized to one of three doses of canakinumab or placebo [ 29 ].

All patients received standard of care therapy. Canakinumab administration resulted in MACE reduction. However, CV mortality was not reduced at any dose. Moreover, canakinumab was associated with a higher incidence of fatal infections compared to placebo.

Thus, CANTOS represented the first major proof-of-concept trial for targeting inflammation in atherosclerosis. This has triggered attempts to seek alternative potential avenues for inflammation inhibition: the inflammatory signaling pathway is complicated and redundant, so blocking a single mediator such as IL-1β may not block all the inflammatory pathways implicated in atherogenesis.

Parallel to CANTOS, the Cardiovascular Inflammation Reduction Trial CIRT assessed low-dose methotrexate in the secondary prevention of atherothrombotic events among patients with a history of myocardial infarction or multivessel coronary artery disease who additionally had either type-2 diabetes or metabolic syndrome.

This trial showed that low-dose methotrexate did not reduce levels of IL-1β, IL-6, or hsCRP and was not associated with fewer MACE than placebo among patients with atherosclerosis whose condition was stable but who were at high risk of CV events. The contradicting results from these two contemporary trials, CANTOS and CIRT, raise a potential hypothesis that adopting anti-inflammatory treatment in the prevention of atherosclerotic CV disease largely depends on the mediators targeted along the rather complex inflammatory cascade.

Inflammasomes are key signaling platforms that detect atherogenic microorganisms and sterile stressors, and activate the highly pro-inflammatory cytokines IL-1β and IL Inhibition of IL-1β and IL-6 signaling, which is initiated at the level of the NLRP3 inflammasome [ 31 ], did effectively reduce atherosclerotic CV outcomes in CANTOS Fig.

While CANTOS targeted patients with residual inflammatory risk median baseline hsCRP 4. Finally, the Low-Dose Colchicine LoDoCo trial tested colchicine in a small randomized trial of patients with stable CAD [ 32 ]; primary results are yet to be confirmed in the larger LoDoCo2 trial ACTRN and Colchicine Cardiovascular Outcomes Trial COLCOT; NCT This may be the case.

Statins have been described to have cholesterol-lowering as well as anti-inflammatory properties and may be advantageous in such conditions, making this class of drugs attractive in multiple diseases. However, this double-edged action is also making it difficult to evaluate if the observed beneficial properties result from cholesterol-lowering properties only, from immunomodulation properties only, or from both with possible interactions between the two [ 33 ].

Because inflammation is the common and driving risk factor in this respect, the main focus should be to control inflammation through low-dose corticosteroids, biologics, or immunosuppressive agents.

However, cholesterol-lowering therapy has also been reported to be beneficial in these conditions [ 36 ]. Multiple auto-inflammatory diseases have been described in which the inflammasome plays an important role [ 37 ]. Familial Mediterranean fever and cryopyrin-associated periodic syndromes are both examples of auto-inflammatory diseases characterized by increased activity of the inflammasome leading to overproduction of IL-1β, which is responsible for the clinical manifestations of these diseases.

The development of anti-IL-1β therapy led to successful treatments for both syndromes [ 38 ]. However, no clear role for cholesterol as a driver or cholesterol-lowering therapy as a treatment has been described yet for these diseases.

Diabetes mellitus DM is unequivocally associated with accelerated atherosclerosis. Patients with type 2 DM have elevated NLRP3 levels in monocytes, increased activity of the inflammasome, and high blood levels of IL-1β and IL Studies have shown that the progression of atherosclerosis in DM involves inappropriate, persistent inflammation induced through excessive inflammasome activation by pathogens and endogenous danger stimuli [ 39 ].

Two months of metformin therapy significantly inhibited the maturation of IL-1β in monocyte-derived macrophages from patients with type 2 DM [ 40 ]. Beyond its hypoglycemic effect, the anti-inflammatory effect of metformin might inhibit the progression of atherosclerosis [ 40 ].

Cholesterol lowering with statins, simultaneously reducing CRP, has proven particularly effective in reducing clinical atherosclerotic events in patients with DM [ 41 ]. Since the introduction of effective antiretroviral therapy in the treatment of human immunodeficiency virus HIV , focus has shifted to preventing HIV-associated comorbidities.

Atherosclerosis-associated CV disease is one of the leading causes of mortality among HIV patients [ 42 ]. There is growing evidence indicating that HIV infection, whether productive or latent, and subsequent inflammatory processes accelerate atherosclerosis [ 43 ]. Antiretroviral therapy reduces atherothrombotic events in HIV patients, but it is not enough to sufficiently prevent CV disease [ 44 ].

As shown, LDL-C induces inflammasome activation, leading to the production of IL-1β and IL, which accelerate atherosclerosis. Therefore, the very recent observation that a genetic variation in the NLRP3 inflammasome gene is associated with not only CV but also total mortality is intriguing hotline presentation by W.

März at the European Atherosclerosis Society, Maastricht, May One could argue that the course of these inflammatory diseases could indeed be influenced by or associated with LDL-C levels, considering the partly similar pathogenesis.

However, although links with enhanced atherosclerosis have been described, no solid evidence is yet found in the literature for a direct causal relationship between LDL-C, inflammasome activation, and the course of these diseases themselves.

Clearly, more research is required. A recent pre-specified sub-study of CANTOS addressed the degree of IL-6 reduction and its relation to CV event reduction [ 47 ].

To optimize patient care, based on previous data and if long-term anti-inflammatory therapy appears safe, we propose an algorithm Fig. There is still a lack of evidence regarding the effect of combining non-statin lipid-lowering medications and novel anti-inflammatory therapy among patients with combined residual risk.

This remains to be elucidated in future clinical studies. Cost-effectiveness will become an important issue here [ 48 , 49 ].

Referring back to the main question addressed by our opinion article: does LDL-C induce inflammation? The answer is yes, it does.

Now, does this matter? Again, yes it does. It is now evident that LDL-C lowering, especially with statins, reduces inflammation and retards atherosclerosis progression. New therapeutic challenges still lie ahead, that will be aided by revolutionary concepts regarding the fundamentals of the biological features of atherosclerosis and the revisited role of inflammation.

Preclinical studies and Mendelian randomization studies paved the way toward establishing a causal link between inflammation and atherosclerosis. The CANTOS represented the strongest proof-of-principle clinical study to support the inflammatory hypothesis of atherosclerosis. However, the latest data from the CIRT, with its negative results, imply that the inflammatory pathway is rather complex and that the adenosine-mediated anti-inflammatory effect of methotrexate might not be as effective as canakinumab at targeting IL-1β.

IL-1β represents the tip of the iceberg; there are several other potential inflammatory mediators that could be directly targeted to halt atherosclerosis progression, such as by directly targeting the inflammasome, IL-1α, IL-6, IL, and IL, among others.

The results of CANTOS encourage further clinical studies evaluating other inflammatory mediators in different clinical settings of secondary prevention, but hurdles still have to be overcome and new avenues explored. IL-6 contributes to atherosclerotic plaque destabilization and is thought to be involved in myocardial injury during ischemia— reperfusion.

In a study assessing the circulating levels of IL-6 receptors and their relation to long-term clinical outcomes in patients with ST-segment elevation myocardial infarction, patients in the highest quartile of IL-6 levels had decreased event-free survival and higher mortality compared with the other lower three quartiles [ 51 ].

An ongoing clinical trial by the same investigators is assessing the effect of anti-IL-6R treatment with tocilizumab in the setting of a ST-segment elevation myocardial infarction ASSAIL-MI trial; NCT Experimental studies have shown that downregulation or inhibition of one or more of the inflammasome components through small interfering RNA reduces the infarct size and preserves myocardial contractility [ 53 , 54 ].

Data on the role of the NLRP3 inflammasome in patients with an acute myocardial infarction or other inflammatory diseases are still scarce. Several experimental drugs targeting different steps along the inflammasome activation cascade are being investigated, including colchicine.

In the search for novel anti-inflammatory strategies, immune cells have been identified as pivotal elements contributing to plaque development and dynamics [ 56 ].

Interest is growing in innate immune cells in light of the recent notion that innate immunity, for a long time considered to be incapable of eliciting an adaptive response i. Risk factors for atherosclerosis promote immune cell migration by pre-activating circulating innate immune cells. Subsequently, innate immune cell activation, mediated by metabolic and epigenetic reprogramming, may perpetuate a systemic low-grade state of inflammation in atherosclerosis.

This knowledge gives rise to new therapeutic modalities in which epigenetic or metabolic modulation of innate immune cells may lead to a decreased rate of chronic systemic inflammation, thereby alleviating atherosclerosis as well as its associated morbidities [ 56 ].

A recently proposed anti-inflammatory mechanism is the therapeutic targeting of co-stimulation [ 57 , 58 ]. By blocking this co-stimulation of antigen presenting cells or T cells, atherosclerosis could be mitigated Fig.

The effects of these co-stimulation blockers on atherosclerosis should be investigated in future clinical studies. However, it should be taken into consideration that blocking co-stimulation could lead to serious adverse effects.

In the context of the complex interplay of the immune system in atherosclerosis, B cells also represent an attractive therapeutic target against atherosclerosis. They exert strong protective and detrimental effects on atherosclerosis progression.

Establishing protective B cell antibody responses is a tempting strategy in halting atherosclerosis progression, either by active vaccination or by passive immunoglobulin transfer [ 60 ].

Recent research has increasingly recognized epigenetic mechanisms associated with atherosclerotic disease. Analysis of human atherosclerotic plaques has demonstrated global DNA hypermethylation, which suggests a strong link between DNA methylation and atherosclerosis development [ 62 ].

This sparked the development of new epigenetic drugs targeting chromatin architecture to halt atherosclerosis. Among these, histone deacetylase inhibitors have demonstrated some preclinical efficacy in experimental models [ 64 , 65 ].

Technical advances in biological approaches such as RNA-sequencing and DNA profiling have paved the way toward an anticipated leap in the development and validation of epigenetic drugs over the coming decades. Co-stimulation blocking as a therapeutic target to diminish atherosclerosis.

Antigen presenting cell orange and T cell blue are depicted with a selection of their receptors. Therapeutic antibodies that may block these receptors are shown in light blue.

Finally, what remains of concern is the safety profile of the emerging anti-inflammatory and immune-modulating medications.

The higher rate of fatal infections with canakinumab and the pro-atherogenic properties of IL-6 inhibitors should be carefully considered. Long-term post-marketing surveillance studies should be continuously conducted to note any potential hazards.

Long-term experience with the application of these anti-inflammatory medications in rheumatologic diseases might provide us with a road map as we approach widespread clinical application in the CV field.

Based on the presented evidence we conclude that LDL-C induces inflammation; inflammation is of proven importance in atherosclerotic disease progression; anti-inflammatory therapies show promise in lowering CV disease risk, especially in selected patients with high remaining inflammatory risk; and intriguing new anti-inflammatory developments, for example, in NLRP3 inflammasome targeting, are currently underway, including novel pathway interventions such as immune cell targeting and epigenetic interference.

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Article CAS PubMed Google Scholar. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. Lindmark E, Diderholm E, Wallentin L, Siegbahn A. That is why some cardiovascular risk prevention researchers are shifting their focus from circulating HDL levels to the actual functional ability of HDL.

Uwe J. Tietge, Ph. In the study, people who did not experience a cardiovascular event demonstrated higher anti-inflammatory HDL levels than participants who did experience a cardiovascular event. It received funding from the Netherlands Organization for Scientific Research and the Swedish Heart-Lung Foundation.

HDL is called good cholesterol because it picks up excess cholesterol in the blood and takes it back to the liver, which breaks it down and helps remove it from the body. HDL can also reduce inflammation in the cells lining blood vessels. This occurs because HDL removes cholesterol stored in macrophage foam cells in atherosclerotic plaques and carries it to the liver.

Atherosclerosis occurs when plaque accumulates on the inner walls of arteries. Plaque is a substance made of cholesterol, calcium, fat, and other molecules.

As plaque deposits grow, they can gradually narrow the blood vessel, reducing blood flow and oxygen delivery to parts of the body or organs. If atherosclerosis is severe enough, it can lead to major health concerns, including stroke, heart attack, and death.

When HDL removes cholesterol from foam cells in plaques, it helps reduce the size of the plaque. By reducing its size, it also reduces the amount of inflammation associated with the plaque. Because of these factors, healthcare professionals typically include circulating HDL levels in many cardiovascular risk assessment tools.

In the new study, the researchers included participants from a larger study: the PREVEND Prevention of Renal and Vascular End Stage Disease Study. The PREVEND Study began in and is investigating the relationship between cardiovascular disease and kidney damage.

The study has about 40, participants, all of whom are adults living in the city of Groningen in Northern Netherlands. From this massive participant pool, the researchers behind the new study selected participants. They excluded people who had experienced a cardiovascular event before the program tracking period.

The researchers used these participants to create case-control pairs of individuals. This meant that there were two groups: an experimental group of people who experienced an initial cardiovascular event during the PREVEND tracking period and people who did not.

Each person in a pair had an age within 5 years of the other. In the study, the researchers defined a cardiovascular event as experiencing a non-fatal or fatal heart attack, receiving a diagnosis of ischemic heart disease, or having surgery to open clogged coronary arteries.

The researchers extracted HDL from participant blood samples and assessed how much it was able to reduce inflammatory responses in endothelial cells, which line blood vessels.

Researchers cholsterol that HDL, or cholestwrol, Nutritional strategies for marathons reduces inflammation. At vholesterol levels, Nutritional strategies for marathons can also reduce the risk of stroke and heart Inflammaiton. So far, intervention trials using medications to improve or increase HDL levels have been unsuccessful. Also, some genetic research indicates that lifelong high or low levels of HDL do not seem to relate to cardiovascular outcomes, as expected. That is why some cardiovascular risk prevention researchers are shifting their focus from circulating HDL levels to the actual functional ability of HDL.

Author: Mazusho

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