C-reactive protein stimulates superoxide anion release and tissue factor activity in vivo

Sridevi Devaraj, Mohan R. Dasu, Uma Singh, L. Vijaya Mohan Rao, Ishwarlal Jialal

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

C-reactive protein (CRP), the prototypic marker of inflammation, is a cardiovascular risk marker and recent in vitro studies suggest that it may promote atherogenesis. CRP promotes oxidative stress in vitro and induces tissue factor (TF) release. However, there is a paucity of data examining the effects of CRP on oxidative stress and tissue factor procoagulant activity (PCA) in vivo. Thus, we tested the effects of CRP administration on superoxide anion release and tissue factor activity and examined mechanistic pathways using a rat sterile air pouch model. Intraperitoneal administration of CRP (20 mg/kg body weight) compared to human serum albumin (HuSA) increased superoxide anion release and tissue factor activity from peritoneal macrophages in vivo (p < 0.01). This was confirmed using intrapouch administration of CRP (25 μg/mL) compared to HuSA. Pretreatment with reactive oxygen species (ROS) scavengers or protein kinase C (PKC) inhibitor significantly abrogated CRP-induced superoxide anion release and tissue factor activity. Pretreatment with extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) inhibitors, but not p38 mitogen-activated protein kinase (p38MAPK) significantly decreased CRP-induced superoxide anion release from macrophages in vivo. CRP-induced tissue factor activity in vivo was abrogated by pretreatment with inhibitors to p38MAPK, JNK and NFκb (nuclear factor-κb), but not ERK. Antibodies to Fc gamma receptors, CD32 and CD64 resulted in significant reduction in CRP-induced superoxide and tissue factor activity in vivo. Thus, CRP appears to induce oxidative stress in vivo by stimulating NADPH oxidase via PKC, ERK and JNK phosphorylation, and induces tissue factor PCA in vivo via upregulation of PKC, p38MAPK, JNK, ROS and NFκb. CRP-induced ROS appears to precede tissue factor release. These effects are abrogated by blocking Fc gamma receptors, CD32 and CD64. This in vivo demonstration provides further evidence for a role for CRP in atherothrombosis.

Original languageEnglish (US)
Pages (from-to)67-74
Number of pages8
JournalAtherosclerosis
Volume203
Issue number1
DOIs
StatePublished - Mar 2009

Fingerprint

Thromboplastin
Superoxides
C-Reactive Protein
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
Phosphotransferases
Protein Kinase C
IgG Receptors
Reactive Oxygen Species
Oxidative Stress
Serum Albumin
Protein C Inhibitor
NADPH Oxidase
Peritoneal Macrophages
Protein Kinase Inhibitors
Atherosclerosis
Up-Regulation
Macrophages
Air
Body Weight

Keywords

  • Macrophages
  • Mechanistic insights
  • Oxidative stress
  • Procoagulant
  • Rat
  • Tissue factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

C-reactive protein stimulates superoxide anion release and tissue factor activity in vivo. / Devaraj, Sridevi; Dasu, Mohan R.; Singh, Uma; Rao, L. Vijaya Mohan; Jialal, Ishwarlal.

In: Atherosclerosis, Vol. 203, No. 1, 03.2009, p. 67-74.

Research output: Contribution to journalArticle

Devaraj, Sridevi ; Dasu, Mohan R. ; Singh, Uma ; Rao, L. Vijaya Mohan ; Jialal, Ishwarlal. / C-reactive protein stimulates superoxide anion release and tissue factor activity in vivo. In: Atherosclerosis. 2009 ; Vol. 203, No. 1. pp. 67-74.
@article{71bf55d100de4c6aa151fcb2b488f53b,
title = "C-reactive protein stimulates superoxide anion release and tissue factor activity in vivo",
abstract = "C-reactive protein (CRP), the prototypic marker of inflammation, is a cardiovascular risk marker and recent in vitro studies suggest that it may promote atherogenesis. CRP promotes oxidative stress in vitro and induces tissue factor (TF) release. However, there is a paucity of data examining the effects of CRP on oxidative stress and tissue factor procoagulant activity (PCA) in vivo. Thus, we tested the effects of CRP administration on superoxide anion release and tissue factor activity and examined mechanistic pathways using a rat sterile air pouch model. Intraperitoneal administration of CRP (20 mg/kg body weight) compared to human serum albumin (HuSA) increased superoxide anion release and tissue factor activity from peritoneal macrophages in vivo (p < 0.01). This was confirmed using intrapouch administration of CRP (25 μg/mL) compared to HuSA. Pretreatment with reactive oxygen species (ROS) scavengers or protein kinase C (PKC) inhibitor significantly abrogated CRP-induced superoxide anion release and tissue factor activity. Pretreatment with extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) inhibitors, but not p38 mitogen-activated protein kinase (p38MAPK) significantly decreased CRP-induced superoxide anion release from macrophages in vivo. CRP-induced tissue factor activity in vivo was abrogated by pretreatment with inhibitors to p38MAPK, JNK and NFκb (nuclear factor-κb), but not ERK. Antibodies to Fc gamma receptors, CD32 and CD64 resulted in significant reduction in CRP-induced superoxide and tissue factor activity in vivo. Thus, CRP appears to induce oxidative stress in vivo by stimulating NADPH oxidase via PKC, ERK and JNK phosphorylation, and induces tissue factor PCA in vivo via upregulation of PKC, p38MAPK, JNK, ROS and NFκb. CRP-induced ROS appears to precede tissue factor release. These effects are abrogated by blocking Fc gamma receptors, CD32 and CD64. This in vivo demonstration provides further evidence for a role for CRP in atherothrombosis.",
keywords = "Macrophages, Mechanistic insights, Oxidative stress, Procoagulant, Rat, Tissue factor",
author = "Sridevi Devaraj and Dasu, {Mohan R.} and Uma Singh and Rao, {L. Vijaya Mohan} and Ishwarlal Jialal",
year = "2009",
month = "3",
doi = "10.1016/j.atherosclerosis.2008.05.060",
language = "English (US)",
volume = "203",
pages = "67--74",
journal = "Atherosclerosis",
issn = "0021-9150",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - C-reactive protein stimulates superoxide anion release and tissue factor activity in vivo

AU - Devaraj, Sridevi

AU - Dasu, Mohan R.

AU - Singh, Uma

AU - Rao, L. Vijaya Mohan

AU - Jialal, Ishwarlal

PY - 2009/3

Y1 - 2009/3

N2 - C-reactive protein (CRP), the prototypic marker of inflammation, is a cardiovascular risk marker and recent in vitro studies suggest that it may promote atherogenesis. CRP promotes oxidative stress in vitro and induces tissue factor (TF) release. However, there is a paucity of data examining the effects of CRP on oxidative stress and tissue factor procoagulant activity (PCA) in vivo. Thus, we tested the effects of CRP administration on superoxide anion release and tissue factor activity and examined mechanistic pathways using a rat sterile air pouch model. Intraperitoneal administration of CRP (20 mg/kg body weight) compared to human serum albumin (HuSA) increased superoxide anion release and tissue factor activity from peritoneal macrophages in vivo (p < 0.01). This was confirmed using intrapouch administration of CRP (25 μg/mL) compared to HuSA. Pretreatment with reactive oxygen species (ROS) scavengers or protein kinase C (PKC) inhibitor significantly abrogated CRP-induced superoxide anion release and tissue factor activity. Pretreatment with extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) inhibitors, but not p38 mitogen-activated protein kinase (p38MAPK) significantly decreased CRP-induced superoxide anion release from macrophages in vivo. CRP-induced tissue factor activity in vivo was abrogated by pretreatment with inhibitors to p38MAPK, JNK and NFκb (nuclear factor-κb), but not ERK. Antibodies to Fc gamma receptors, CD32 and CD64 resulted in significant reduction in CRP-induced superoxide and tissue factor activity in vivo. Thus, CRP appears to induce oxidative stress in vivo by stimulating NADPH oxidase via PKC, ERK and JNK phosphorylation, and induces tissue factor PCA in vivo via upregulation of PKC, p38MAPK, JNK, ROS and NFκb. CRP-induced ROS appears to precede tissue factor release. These effects are abrogated by blocking Fc gamma receptors, CD32 and CD64. This in vivo demonstration provides further evidence for a role for CRP in atherothrombosis.

AB - C-reactive protein (CRP), the prototypic marker of inflammation, is a cardiovascular risk marker and recent in vitro studies suggest that it may promote atherogenesis. CRP promotes oxidative stress in vitro and induces tissue factor (TF) release. However, there is a paucity of data examining the effects of CRP on oxidative stress and tissue factor procoagulant activity (PCA) in vivo. Thus, we tested the effects of CRP administration on superoxide anion release and tissue factor activity and examined mechanistic pathways using a rat sterile air pouch model. Intraperitoneal administration of CRP (20 mg/kg body weight) compared to human serum albumin (HuSA) increased superoxide anion release and tissue factor activity from peritoneal macrophages in vivo (p < 0.01). This was confirmed using intrapouch administration of CRP (25 μg/mL) compared to HuSA. Pretreatment with reactive oxygen species (ROS) scavengers or protein kinase C (PKC) inhibitor significantly abrogated CRP-induced superoxide anion release and tissue factor activity. Pretreatment with extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) inhibitors, but not p38 mitogen-activated protein kinase (p38MAPK) significantly decreased CRP-induced superoxide anion release from macrophages in vivo. CRP-induced tissue factor activity in vivo was abrogated by pretreatment with inhibitors to p38MAPK, JNK and NFκb (nuclear factor-κb), but not ERK. Antibodies to Fc gamma receptors, CD32 and CD64 resulted in significant reduction in CRP-induced superoxide and tissue factor activity in vivo. Thus, CRP appears to induce oxidative stress in vivo by stimulating NADPH oxidase via PKC, ERK and JNK phosphorylation, and induces tissue factor PCA in vivo via upregulation of PKC, p38MAPK, JNK, ROS and NFκb. CRP-induced ROS appears to precede tissue factor release. These effects are abrogated by blocking Fc gamma receptors, CD32 and CD64. This in vivo demonstration provides further evidence for a role for CRP in atherothrombosis.

KW - Macrophages

KW - Mechanistic insights

KW - Oxidative stress

KW - Procoagulant

KW - Rat

KW - Tissue factor

UR - http://www.scopus.com/inward/record.url?scp=60649120010&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=60649120010&partnerID=8YFLogxK

U2 - 10.1016/j.atherosclerosis.2008.05.060

DO - 10.1016/j.atherosclerosis.2008.05.060

M3 - Article

C2 - 18621373

AN - SCOPUS:60649120010

VL - 203

SP - 67

EP - 74

JO - Atherosclerosis

JF - Atherosclerosis

SN - 0021-9150

IS - 1

ER -