Potential Role of Protein Disulfide Isomerase in Metabolic Syndrome‐Derived Platelet Hyperactivity

Gaspar, Renato Simões; Trostchansky, Andrés; Paes, Antonio Marcus de Andrade

doi:10.1155/2016/2423547

Cited by 16 publications

(17 citation statements)

References 104 publications

(129 reference statements)

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“…Platelet activation, as evidenced by platelet indices, is a recognized phenomenon in metabolic syndrome [73,74]. This study resulted in a positive association between PC and morbid obesity, and a negative association between MCV and obesity and morbid obesity.…”

Section: Discussionmentioning

confidence: 91%

GWAS and PheWAS of red blood cell components in a Northern Nevadan cohort

et al. 2019

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In this study, we perform a full genome-wide association study (GWAS) to identify statistically significantly associated single nucleotide polymorphisms (SNPs) with three red blood cell (RBC) components and follow it with two independent PheWASs to examine associations between phenotypic data (case-control status of diagnoses or disease), significant SNPs, and RBC component levels. We first identified associations between the three RBC components: mean platelet volume (MPV), mean corpuscular volume (MCV), and platelet counts (PC), and the genotypes of approximately 500,000 SNPs on the Illumina Infimum DNA Human OmniExpress-24 BeadChip using a single cohort of 4,673 Northern Nevadans. Twenty-one SNPs in five major genomic regions were found to be statistically significantly associated with MPV, two regions with MCV, and one region with PC, with p <5x10 -8 . Twenty-nine SNPs and nine chromosomal regions were identified in 30 previous GWASs, with effect sizes of similar magnitude and direction as found in our cohort. The two strongest associations were SNP rs1354034 with MPV ( p = 2.4x10 -13 ) and rs855791 with MCV ( p = 5.2x10 -12 ). We then examined possible associations between these significant SNPs and incidence of 1,488 phenotype groups mapped from International Classification of Disease version 9 and 10 (ICD9 and ICD10) codes collected in the extensive electronic health record (EHR) database associated with Healthy Nevada Project consented participants. Further leveraging data collected in the EHR, we performed an additional PheWAS to identify associations between continuous red blood cell (RBC) component measures and incidence of specific diagnoses. The first PheWAS illuminated whether SNPs associated with RBC components in our cohort were linked with other hematologic phenotypic diagnoses or diagnoses of other nature. Although no SNPs from our GWAS were identified as strongly associated to other phenotypic components, a number of associations were identified with p -values ranging between 1x10 -3 and 1x10 -4 with traits such as respiratory failure, sleep disorders, hypoglycemia, hyperglyceridemia, GERD and IBS. The second PheWAS examined possible phenotypic predictors of abnormal RBC component measures: a number of hematologic phenotypes such as thrombocytopenia, anemias, hemoglobinopathies and pancytopenia were found to be strongly associated to RBC component measures; additional phenotypes such as (morbid) obesity, malaise and fatigue, alcoholism, and cirrhosis were also identified to be possible predictors of RBC component measures.

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Section: Discussionmentioning

confidence: 91%

GWAS and PheWAS of red blood cell components in a Northern Nevadan cohort

et al. 2019

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“…Oxidative stress can also modify reactions involving disulfide bond formation, which can lead to activation or inactivation of a number of proteins implicated in different cellular pathways. For example, oxidative stress increases the activity of platelet membrane protein disulfide isomerase which activates several integrins by disulfide bond isomerization (44). The most important among these is the α IIb β 3 integrin, which undergoes partial reduction of disulfide bonds during activation (44–47).…”

Section: Relationship Between Oxidative Stress Aging and Platelet Hmentioning

confidence: 99%

“…For example, oxidative stress increases the activity of platelet membrane protein disulfide isomerase which activates several integrins by disulfide bond isomerization (44). The most important among these is the α IIb β 3 integrin, which undergoes partial reduction of disulfide bonds during activation (44–47). Disruption of this finely-tuned balance in α IIb β 3 integrin activation can thus lead to altered thrombotic susceptibility (47).…”

Section: Relationship Between Oxidative Stress Aging and Platelet Hmentioning

confidence: 99%

Platelet Function in Aging

Blanc

Lordkipanidzé

2019

Front. Cardiovasc. Med.

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Aging is associated with an increased incidence of cardiovascular disease and thrombosis. Platelets play a major role in maintaining hemostasis and in thrombus formation, making them a key player in thrombotic disorders. Whereas it is well-known that platelet aggregability is increased in vascular diseases, the contribution of age-related changes in platelet biology to cardiovascular risk is not well-understood. Several lines of evidence support that platelets from older subjects differ in their function and structure, making platelets more prone to activation and less sensitive to inhibition. These age-related changes could lead to platelet hyperactivity and to the development of a prothrombotic state in advanced age. This review will focus on platelet biochemical modifications during aging and on the mechanisms by which these alterations could lead to thrombotic disease.

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“…Both PDI and Nox-1 contribute to oxidative stress observed in individuals with cardiometabolic risk factors. Indeed, we have previously proposed that platelet PDI could be implicated in platelet hyperactivation found in obesity [ 20 ]. In addition, PDI expression has been shown to be elevated in atherosclerotic lesions [ 12 ], while Nox-1 is reported to be upregulated in mesenteric arteries of mice with metabolic syndrome and contributes to vasodilation of these vessels [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors

et al. 2021

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Background: Protein disulphide isomerase (PDI) and NADPH oxidase 1 (Nox-1) regulate platelet function and reactive oxygen species (ROS) generation, suggesting potentially interdependent roles. Increased platelet reactivity and ROS production have been correlated with cardiometabolic disease risk factors. Objectives: To establish whether PDI and Nox-1 cooperate to control platelet function. Methods: Immunofluorescence microscopy was utilised to determine expression and localisation of PDI and Nox-1. Platelet aggregation, fibrinogen binding, P-selectin exposure, spreading and calcium mobilization were measured as markers of platelet function. A cross-sectional population study (n = 136) was conducted to assess the relationship between platelet PDI and Nox-1 levels and cardiometabolic risk factors. Results: PDI and Nox-1 co-localized upon activation induced by the collagen receptor GPVI. Co-inhibition of PDI and Nox-1 led to additive inhibition of GPVI-mediated platelet aggregation, activation and calcium flux. This was confirmed in murine Nox-1−/− platelets treated with PDI inhibitor bepristat, without affecting bleeding. PDI and Nox-1 together contributed to GPVI signalling that involved the phosphorylation of p38 MAPK, p47phox, PKC and Akt. Platelet PDI and Nox-1 levels were upregulated in obesity, with platelet Nox-1 also elevated in hypertensive individuals. Conclusions: We show that PDI and Nox-1 cooperate to control platelet function and are associated with cardiometabolic risk factors.

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Potential Role of Protein Disulfide Isomerase in Metabolic Syndrome‐Derived Platelet Hyperactivity

Cited by 16 publications

References 104 publications

GWAS and PheWAS of red blood cell components in a Northern Nevadan cohort

GWAS and PheWAS of red blood cell components in a Northern Nevadan cohort

Platelet Function in Aging

Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors

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