Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke

Leskelä, Jaakko; Toppila, Iiro; Härma, Mari‐Anne; Palviainen, Teemu; Salminen, Aino; Sandholm, Niina; Pietiäinen, Milla; Kopra, Elisa; Barros, Jean‐Paul Pais de; Lassenius, Mariann I.; Kumar, Anmol; Harjutsalo, Valma; Roslund, Kajsa; Loukola, Anu; Havulinna, Aki S.; Lagrost, Laurent; Salomaa, Veikko; Groop, Per‐Henrik; Perola, Markus; Kaprio, Jaakko; Lehto, Markku; Pussinen, Pirkko J.

doi:10.1161/jaha.121.022482

Cited by 12 publications

(12 citation statements)

References 48 publications

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“…Genetic polymorphisms contributing to serum lipopolysaccharide activity were associated with the risk of “ischemic stroke,” “any stroke,” “TOAST small artery occlusion,” “TOAST cardioaortic embolism,” and “intracranial aneurysm” in the Megastroke population, whereas the genetic risk score of lipopolysaccharide activity presented associations with deep vein thrombosis, pulmonary embolism, and venous thromboembolism 117 . Even a causal association of lipopolysaccharide in stroke was suggested in this study, which is the first one exploring the genetic background of endotoxemia 117 …”

Section: Discussionmentioning

confidence: 99%

“…Finnish subjects. 117 Altogether, the genome-wide association study found 741 single-nucleotide polymorphisms in five independent loci in chromosomes 3, 4, 5, 11, and 15, which explained up to 9.2% of the lipopolysaccharide activity variation. The loci were associated with expression of genes KNG1 (kininogen-1), F11/KLKB1 (FXI/kallikrein), F12 (FXII), SERPING1 (plasma protease C1 inhibitor), and LIPC (hepatic lipase).…”

Section: Geneticsmentioning

confidence: 96%

“…Inflammation may derive from endotoxemia, which is a risk factor for chronic cardiometabolic disorders, such as obesity, nonalcoholic fatty liver disease, metabolic syndrome, insulin resistance, type 2 diabetes, dyslipidemia, and cardiovascular diseases 5,8,112‐116 (Figure 4). At least for thromboembolic events and stroke, the association seems to be causal 117 . Inflammatory markers associated with periodontitis and cardiometabolic disorders largely overlap.…”

Section: Endotoxemiamentioning

confidence: 99%

“…Common missense mutations in the toll‐like receptor 4 receptor are associated with a phenotype hyporesponsive to inhaled lipopolysaccharide, 185 and an intergenic cluster located in 7p11.2 is associated with lipopolysaccharide‐induced febrile response 186 . However, neither of these genetic variations were among those associating with endotoxemia on a genome‐wide level in over 11 000 Finnish subjects 117 . Altogether, the genome‐wide association study found 741 single‐nucleotide polymorphisms in five independent loci in chromosomes 3, 4, 5, 11, and 15, which explained up to 9.2% of the lipopolysaccharide activity variation.…”

Section: Endotoxemia and Cardiometabolic Disordersmentioning

confidence: 99%

“…At least for thromboembolic events and stroke, the association seems to be causal. 117 Inflammatory markers associated with periodontitis and cardiometabolic disorders largely overlap. Also, molecular mimicry caused by cross-reactive autoantibodies promotes inflammation linking periodontitis with cardiometabolic disorders.…”

Section: Endotoxemiamentioning

confidence: 99%

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Periodontitis and cardiometabolic disorders: The role of lipopolysaccharide and endotoxemia

Pussinen

Kopra

Pietiäinen

et al. 2022

Periodontology 2000

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Lipopolysaccharide is an important virulence factor of gramnegative bacteria. It is often referred to as endotoxin, which is used synonymously with lipopolysaccharide, although there are a few endotoxins that are not lipopolysaccharides. 1 Virulence is determined as the strength of the pathogenic potential, referring to the relative capacity of a microbe to cause damage in the host and the ability to overcome host defenses. 2 Several virulence factors or characteristics contribute to the ability of a microbe to cause disease. For example, fimbriae, adhesins, and invasins promote colonization, growth, attachment, and invasiveness. Other factors, such as toxins and proteases, are more immunoinhibitory or immunosuppressive and contribute to tissue-destructive capacity and evasion of host responses. Also, the susceptibility of the host plays a role in infections.Lipopolysaccharide resides in the outer membrane of the bacteria, where its hydrophobic structures composed of fatty acid chains anchor the molecule into the bacterial membrane, and the hydrophilic portion (ie the rest of the molecule) projects from the membrane. Lipopolysaccharide is a potent activator of innate and adaptive immune responses, as well as of tissue destruction cascades. It plays a major role in the pathogenesis of periodontitis, where an abundant number of gram-negative species is a typical determinant of the periodontal microbiota.Translocation of lipopolysaccharide to the bloodstream causes endotoxemia (ie, lipopolysaccharide activity present in serum/ plasma). An approximate twofold increase of lipopolysaccharide activity in apparently healthy subjects is considered 'metabolic endotoxemia,' which has been associated with unhealthy nutrition. 3 Circulating endotoxin is alternatively called 'intestinal endotoxemia,' referring to its presumed source, the gastrointestinal tract. The levels reported, for example, among healthy blood donors, middle-aged subjects, or healthy elderly subjects have been 0.3 pg/ml, 1.2 pg/ml, and 6.7 pg/ml, respectively. [4][5][6] The corresponding level may reach 850 pg/ml in gram-negative septic shock caused by lipopolysaccharide. 7 Human cells expressing the lipopolysaccharide receptor complex are highly sensitive and can respond in minutes to picograms per milliliter of lipopolysaccharide. Chronic endotoxemia is involved in the pathogenesis of many inflammation-driven conditions, especially cardiometabolic disorders, including atherosclerotic cardiovascular diseases, obesity, liver diseases, diabetes, and metabolic syndrome,e 8 and thus it is regarded as a risk factor.Periodontitis patients are known to have increased circulating lipopolysaccharide activity and metabolic disturbances, which may be either the cause or effect of endotoxemia. Observations that bacteria disseminate into circulation after toothbrushing and periodontal procedures 9,10 and assumptions that endotoxin may disseminate through inflamed periodontium and bleeding gums support the This is an open access article under the terms of the Creative ...

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Section: Discussionmentioning

confidence: 99%

Section: Geneticsmentioning

confidence: 96%

Section: Endotoxemiamentioning

confidence: 99%

Section: Endotoxemia and Cardiometabolic Disordersmentioning

confidence: 99%

Section: Endotoxemiamentioning

confidence: 99%

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Periodontitis and cardiometabolic disorders: The role of lipopolysaccharide and endotoxemia

Pussinen

Kopra

Pietiäinen

et al. 2022

Periodontology 2000

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Dual Functioned Hexapeptide‐Coated Lipid‐Core Nanomicelles Suppress Toll‐Like Receptor‐Mediated Inflammatory Responses through Endotoxin Scavenging and Endosomal pH Modulation

Sun

Liu

et al. 2023

Advanced Science

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Excessive activation of Toll‐like receptor (TLR) signaling pathways and the circulating endotoxin are key players in the pathogenesis of many acute and chronic inflammatory diseases. Regulation of TLR‐mediated inflammatory responses by bioactive nanodevices represents a promising strategy for treating these diseases. In searching for novel, clinically applicable nanodevices with potent TLR inhibitory activities, three types of hexapeptide‐modified nano‐hybrids with different cores of phospholipid nanomicelles, liposomes, and poly(lactic‐co‐glycolic acid) nanoparticles are constructed. Interestingly, only the peptide‐modified lipid–core nanomicelles (M‐P12) display potent TLR inhibitory activities. Further mechanistic studies disclose that lipid–core nanomicelles have a generic property to bind to and scavenge lipophilic TLR ligands including lipopolysaccharide to block the ligand–receptor interaction and down‐regulate the TLR signaling extracellularly. In addition, the peptide modification enables M‐P12 a unique capability to modulate endosomal acidification upon being endocytosed into macrophages, which subsequently regulates the endosomal TLR signal transduction. In an acute lung injury mouse model, intratracheal administration of M‐P12 can effectively target lung macrophages and reduce lung inflammation and injuries. This work defines a dual mechanism of action of the peptide‐modified lipid–core nanomicelles in regulating TLR signaling, and provides new strategies for the development of therapeutic nanodevices for treating inflammatory diseases.

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Impaired fibrinolysis in patients with atrial fibrillation and elevated circulating lipopolysaccharide

Sadowski,

Ząbczyk,

Undas

2024

J Thromb Thrombolysis

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It is unknown whether elevated gut-derived serum lipopolysaccharide (LPS) can affect thrombin generation, fibrinolysis, and fibrin clot properties in atrial fibrillation (AF). We aimed to evaluate associations of circulating LPS with prothrombotic markers in AF patients. A total of 157 (women, 57.3%) ambulatory anticoagulant-naïve AF patients aged from 42 to 86 years were recruited. Clinical data together with serum LPS, inflammation, endothelial injury, coagulation and fibrinolysis markers, including fibrin clot permeability (Ks) and clot lysis time (CLT), were analyzed. A median LPS concentration was 73.0 (58.0-100.0) pg/mL and it showed association with CLT (r = 0.31, p < 0.001) and plasminogen activator inhibitor-1 (PAI-1, r = 0.57, p < 0.001), but not other fibrinolysis proteins, thrombin generation, inflammatory markers, or Ks. There were weak associations of LPS with von Willebrand factor (vWF, r = 0.2, p = 0.013), cardiac troponin I (r = 0.16, p = 0.045), and growth differentiation factor-15 (r = 0.27, p < 0.001). No associations of LPS and CHA2DS2-VASc or other clinical variables were observed. Multivariable regression adjusted for potential confounders showed that serum LPS ≥ 100 pg/mL was an independent predictor of prolonged CLT. This study is the first to demonstrate antifibrinolytic effects of elevated LPS in AF patients largely driven by enhanced PAI-1 release.

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Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke

Cited by 12 publications

References 48 publications

Periodontitis and cardiometabolic disorders: The role of lipopolysaccharide and endotoxemia

Periodontitis and cardiometabolic disorders: The role of lipopolysaccharide and endotoxemia

Dual Functioned Hexapeptide‐Coated Lipid‐Core Nanomicelles Suppress Toll‐Like Receptor‐Mediated Inflammatory Responses through Endotoxin Scavenging and Endosomal pH Modulation

Impaired fibrinolysis in patients with atrial fibrillation and elevated circulating lipopolysaccharide

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