Apolipoprotein E genotype is related to nitric oxide production in platelets

Marcourakis, Tânia; Bahia, Valéria Santoro; Kawamoto, Elisa Mitiko; Munhoz, Carolina Demarchi; Gorjão, Renata; Artes, Rinaldo; Kok, Fernando; Caramelli, Paulo; Nitrini, Ricardo; Curi, Rui; Scavone, Cristóforo

doi:10.1002/cbf.1516

Cited by 17 publications

(11 citation statements)

References 51 publications

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“…30, 33 Conversely, apoE protein inhibits platelet aggregation through induction of platelet nitric oxide, 32 a phenomenon that may be altered in APO deficient mice display 4 + subjects. 31 Increased cholesterol loading of platelets in mice causes platelet hyperreactivity as well as thrombocytopenia due to increased platelet clearance. 34, 35 Our finding of increased lipid rafts in APOε4 + monocytes, together with past reports that apoE4 protein is defective in promoting cholesterol efflux from cells, 20 raises the interesting possibility that the APOε4 genotype may confer abnormalities in platelet function and number through effects upon platelet cholesterol.…”

Section: Discussionmentioning

confidence: 99%

APOε4 is associated with enhanced in vivo innate immune responses in human subjects

Gale¹,

Gao²,

Mikacenic³

et al. 2014

Journal of Allergy and Clinical Immunology

159

145

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Background The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (apo)E, a lipid-trafficking protein that impacts inflammation, has well-described ‘wild type’ (ε3) and disease-associated (ε2, ε4) alleles, but its connection to human innate immunity is undefined. Objective To define the relationship of APOε4 to the human innate immune response. Methods We evaluated APOε4 in several functional models of the human innate immune response including intravenous lipopolysaccharide challenge in human subjects, and assessed APOε4 association to organ injury in human severe sepsis, a disease driven by dysregulated innate immunity. Results Whole blood from healthy APOε3/APOε4 volunteers induced higher cytokines upon ex vivo stimulation with Toll like Receptor (TLR)2, TLR4, or TLR5 ligands than blood from APOε3/APOε3 subjects, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3/APOε3 and APOε3/APOε4 serum neutralized lipopolysaccharide equivalently and supported similar lipopolysaccharide responses in Apoe-deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous lipopolysaccharide, APOε3/APOε4 human subjects had higher hyperthermia and plasma TNFα and earlier plasma IL-6 than APOε3/APOε3 subjects. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury, and altered splenic lymphocyte apoptosis after systemic lipopolysaccharide compared with APOE3 counterparts. In a cohort of 828 severe sepsis patients, APOε4 was associated with increased coagulation system failure among European American subjects. Conclusions APOε4 is a determinant of the human innate immune response to multiple TLR ligands, and associates with altered patterns of organ injury in human sepsis.

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Section: Discussionmentioning

confidence: 99%

APOε4 is associated with enhanced in vivo innate immune responses in human subjects

Gale¹,

Gao²,

Mikacenic³

et al. 2014

Journal of Allergy and Clinical Immunology

159

145

View full text Add to dashboard Cite

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“…Its catalytic α subunit is sensitive to damage by free radicals and it has been described that ONOO − can cause cell membrane damage, which in turn leads to the disruption of Na,K-ATPase activity (Xie et al 1995;Gloor 1997;Kim and Ko 1998). In addition, studies also showed that APOE e4 allele carriers has higher platelet NOS activity than non-carriers in AD patients when compared to aged controls (Marcourakis et al 2008). The results presented by (Kawamoto et al 2007) demonstrated a disruption in systemic modulation of oxidative stress in aging and with more intensity in AD and are consistent with the suggestion that neurodegeneration and aging could share a common pathogenic pathway.…”

Section: Discussionmentioning

confidence: 99%

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

Kawamoto

Vasconcelos

Degaspari

et al. 2012

AGE

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Aging is associated with an increased susceptibility to neurodegenerative disorders which has been linked to chronic inflammation. This process generates oxygen-reactive species, ultimately responsible for a process known as oxidative stress, leading to changes in nitric oxide (NO), and cyclic guanosine monophosphate (cyclic GMP) signaling pathway. In previous studies, we showed that human aging was associated with an increase in NO Synthase (NOS) activity, a decrease in basal cyclic GMP levels in human platelets, and an increase in thiobarbituric acid-reactant substances (TBARS) in erythrocytes. The aim of the present work was to evaluate NOS activity, TBARS and cyclic GMP levels in hippocampus and frontal cortex and its correlation to platelets and erythrocytes of 4-, 12-, and 24-month-old rats. The result showed an age-related decrease in cyclic GMP levels which was linked to an increase in NOS activity and TBARS in both central areas as well as in platelets and erythrocytes of rats. The present data confirmed our previous studies performed in human platelets and erythrocytes and validate NOS activity and cyclic GMP in human platelet as well as TBARS in erythrocytes as biomarkers to study agerelated disorders and new anti-aging therapies.

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“…Very few investigators have addressed markers of oxidative stress in platelets. Marcourakis et al [51] studied the content of thiobarbituric acid-reactive substances in platelets from AD patients, and found evidence of increased lipid peroxidation, NOS and Na + , K + -ATPase activity, as compared to controls. In addition, increased platelet NOS activity was higher in carriers of the APOE epsilon-4 allele as compared to non-carriers.…”

Section: Free Radicals and Markers Of Oxidative Stressmentioning

confidence: 99%

Platelet biomarkers in Alzheimer’s disease

Talib

Joaquim²,

Forlenza³

2012

WJP

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The search for diagnostic and prognostic markers in Alzheimer's disease (AD) has been an area of active research in the last decades. Biochemical markers are correlates of intracerebral changes that can be identified in biological fluids, namely: peripheral blood (total blood, red and white blood cells, platelets, plasma and serum), saliva, urine and cerebrospinal fluid. An important feature of a biomarker is that it can be measured objectively and evaluated as (1) an indicator of disease mechanisms (markers of core pathogenic processes or the expression of downstream effects of these processes), or (2) biochemical responses to pharmacological or therapeutic intervention, which can be indicative of disease modification. Platelets have been used in neuropharmacological models since the mid-fifties, as they share several homeostatic functions with neurons, such as accumulation and release of neurotransmitters, responsiveness to variations in calcium concentration, and expression of membrane-bound compounds. Recent studies have shown that platelets also express several components related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress: thus they can be used in the search for biomarkers of the disease process. For instance, platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B. Moreover, platelets express enzymes involved in membrane homeostasis (e.g., phospholipase A2), and markers of the inflammatory process and oxidative stress. In this review we summarize the available literature and discuss evidence concerning the potential use of platelet markers in AD.

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Apolipoprotein E genotype is related to nitric oxide production in platelets

Cited by 17 publications

References 51 publications

APOε4 is associated with enhanced in vivo innate immune responses in human subjects

APOε4 is associated with enhanced in vivo innate immune responses in human subjects

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

Platelet biomarkers in Alzheimer’s disease

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