Fortilin reduces apoptosis in macrophages and promotes atherosclerosis

Decha Pinkaew, Rachel J. Le, Yanjie Chen, Mahmoud Eltorky, Ba Bie Teng, Kenichi Fujise

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Atherosclerosis, a deadly disease insufficiently addressed by cholesterol-lowering drugs, needs new therapeutic strategies. Fortilin, a 172-amino acid multifunctional polypeptide, binds p53 and blocks its transcriptional activation of Bax, thereby exerting potent antiapoptotic activity. Although fortilin-overexpressing mice reportedly exhibit hypertension and accelerated atherosclerosis, it remains unknown if fortilin, not hypertension, facilitates atherosclerosis. Our objective was to test the hypothesis that fortilin in and of itself facilitates atherosclerosis by protecting macrophages against apoptosis. We generated fortilindeficient (fortilin-/-) mice and wild-type counterparts (fortilin-/-) on a LDL receptor (Ldlr)-/- apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec1)-/- hypercholesterolemic genetic background, incubated them for 10 mo on a normal chow diet, and assessed the degree and extent of atherosclerosis. Despite similar blood pressure and lipid profiles, fortilin-/- mice exhibited significantly less atherosclerosis in their aortae than their fortilin-/- littermate controls. Quantitative immunostaining and flow cytometry analyses showed that the atherosclerotic lesions of fortilin-/- mice contained fewer macrophages than those of fortilin-/- mice. In addition, there were more apoptotic cells in the intima of fortilin-/- mice than in the intima of fortilin-/- mice. Furthermore, peritoneal macrophages from fortilin-/- mice expressed more Bax and underwent increased apoptosis, both at the baseline level and in response to oxidized LDL. Finally, hypercholesterolemic sera from Ldlr-/-Apobec1-/- mice induced fortilin in peritoneal macrophages more robustly than sera from control mice. In conclusion, fortilin, induced in the proatherosclerotic microenvironment in macrophages, protects macrophages against Bax-induced apoptosis, allows them to propagate, and accelerates atherosclerosis. Anti-fortilin therapy thus may represent a promising next generation antiatherosclerotic therapeutic strategy.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume305
Issue number10
DOIs
StatePublished - Nov 15 2013

Fingerprint

Atherosclerosis
Macrophages
Apoptosis
LDL Receptors
Peritoneal Macrophages
Hypertension
Serum
Transcriptional Activation
Aorta
Flow Cytometry
Therapeutics
Cholesterol
Diet
Blood Pressure
Lipids
Amino Acids
Peptides
Pharmaceutical Preparations

Keywords

  • Apoptosis
  • Atherosclerosis
  • Fortilin
  • Macrophages

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Fortilin reduces apoptosis in macrophages and promotes atherosclerosis. / Pinkaew, Decha; Le, Rachel J.; Chen, Yanjie; Eltorky, Mahmoud; Teng, Ba Bie; Fujise, Kenichi.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 305, No. 10, 15.11.2013.

Research output: Contribution to journalArticle

@article{a3ba73e2ecb6429cb2f76993275f30c9,
title = "Fortilin reduces apoptosis in macrophages and promotes atherosclerosis",
abstract = "Atherosclerosis, a deadly disease insufficiently addressed by cholesterol-lowering drugs, needs new therapeutic strategies. Fortilin, a 172-amino acid multifunctional polypeptide, binds p53 and blocks its transcriptional activation of Bax, thereby exerting potent antiapoptotic activity. Although fortilin-overexpressing mice reportedly exhibit hypertension and accelerated atherosclerosis, it remains unknown if fortilin, not hypertension, facilitates atherosclerosis. Our objective was to test the hypothesis that fortilin in and of itself facilitates atherosclerosis by protecting macrophages against apoptosis. We generated fortilindeficient (fortilin-/-) mice and wild-type counterparts (fortilin-/-) on a LDL receptor (Ldlr)-/- apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec1)-/- hypercholesterolemic genetic background, incubated them for 10 mo on a normal chow diet, and assessed the degree and extent of atherosclerosis. Despite similar blood pressure and lipid profiles, fortilin-/- mice exhibited significantly less atherosclerosis in their aortae than their fortilin-/- littermate controls. Quantitative immunostaining and flow cytometry analyses showed that the atherosclerotic lesions of fortilin-/- mice contained fewer macrophages than those of fortilin-/- mice. In addition, there were more apoptotic cells in the intima of fortilin-/- mice than in the intima of fortilin-/- mice. Furthermore, peritoneal macrophages from fortilin-/- mice expressed more Bax and underwent increased apoptosis, both at the baseline level and in response to oxidized LDL. Finally, hypercholesterolemic sera from Ldlr-/-Apobec1-/- mice induced fortilin in peritoneal macrophages more robustly than sera from control mice. In conclusion, fortilin, induced in the proatherosclerotic microenvironment in macrophages, protects macrophages against Bax-induced apoptosis, allows them to propagate, and accelerates atherosclerosis. Anti-fortilin therapy thus may represent a promising next generation antiatherosclerotic therapeutic strategy.",
keywords = "Apoptosis, Atherosclerosis, Fortilin, Macrophages",
author = "Decha Pinkaew and Le, {Rachel J.} and Yanjie Chen and Mahmoud Eltorky and Teng, {Ba Bie} and Kenichi Fujise",
year = "2013",
month = "11",
day = "15",
doi = "10.1152/ajpheart.00570.2013",
language = "English (US)",
volume = "305",
journal = "American Journal of Physiology - Endocrinology and Metabolism",
issn = "0193-1849",
publisher = "American Physiological Society",
number = "10",

}

TY - JOUR

T1 - Fortilin reduces apoptosis in macrophages and promotes atherosclerosis

AU - Pinkaew, Decha

AU - Le, Rachel J.

AU - Chen, Yanjie

AU - Eltorky, Mahmoud

AU - Teng, Ba Bie

AU - Fujise, Kenichi

PY - 2013/11/15

Y1 - 2013/11/15

N2 - Atherosclerosis, a deadly disease insufficiently addressed by cholesterol-lowering drugs, needs new therapeutic strategies. Fortilin, a 172-amino acid multifunctional polypeptide, binds p53 and blocks its transcriptional activation of Bax, thereby exerting potent antiapoptotic activity. Although fortilin-overexpressing mice reportedly exhibit hypertension and accelerated atherosclerosis, it remains unknown if fortilin, not hypertension, facilitates atherosclerosis. Our objective was to test the hypothesis that fortilin in and of itself facilitates atherosclerosis by protecting macrophages against apoptosis. We generated fortilindeficient (fortilin-/-) mice and wild-type counterparts (fortilin-/-) on a LDL receptor (Ldlr)-/- apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec1)-/- hypercholesterolemic genetic background, incubated them for 10 mo on a normal chow diet, and assessed the degree and extent of atherosclerosis. Despite similar blood pressure and lipid profiles, fortilin-/- mice exhibited significantly less atherosclerosis in their aortae than their fortilin-/- littermate controls. Quantitative immunostaining and flow cytometry analyses showed that the atherosclerotic lesions of fortilin-/- mice contained fewer macrophages than those of fortilin-/- mice. In addition, there were more apoptotic cells in the intima of fortilin-/- mice than in the intima of fortilin-/- mice. Furthermore, peritoneal macrophages from fortilin-/- mice expressed more Bax and underwent increased apoptosis, both at the baseline level and in response to oxidized LDL. Finally, hypercholesterolemic sera from Ldlr-/-Apobec1-/- mice induced fortilin in peritoneal macrophages more robustly than sera from control mice. In conclusion, fortilin, induced in the proatherosclerotic microenvironment in macrophages, protects macrophages against Bax-induced apoptosis, allows them to propagate, and accelerates atherosclerosis. Anti-fortilin therapy thus may represent a promising next generation antiatherosclerotic therapeutic strategy.

AB - Atherosclerosis, a deadly disease insufficiently addressed by cholesterol-lowering drugs, needs new therapeutic strategies. Fortilin, a 172-amino acid multifunctional polypeptide, binds p53 and blocks its transcriptional activation of Bax, thereby exerting potent antiapoptotic activity. Although fortilin-overexpressing mice reportedly exhibit hypertension and accelerated atherosclerosis, it remains unknown if fortilin, not hypertension, facilitates atherosclerosis. Our objective was to test the hypothesis that fortilin in and of itself facilitates atherosclerosis by protecting macrophages against apoptosis. We generated fortilindeficient (fortilin-/-) mice and wild-type counterparts (fortilin-/-) on a LDL receptor (Ldlr)-/- apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec1)-/- hypercholesterolemic genetic background, incubated them for 10 mo on a normal chow diet, and assessed the degree and extent of atherosclerosis. Despite similar blood pressure and lipid profiles, fortilin-/- mice exhibited significantly less atherosclerosis in their aortae than their fortilin-/- littermate controls. Quantitative immunostaining and flow cytometry analyses showed that the atherosclerotic lesions of fortilin-/- mice contained fewer macrophages than those of fortilin-/- mice. In addition, there were more apoptotic cells in the intima of fortilin-/- mice than in the intima of fortilin-/- mice. Furthermore, peritoneal macrophages from fortilin-/- mice expressed more Bax and underwent increased apoptosis, both at the baseline level and in response to oxidized LDL. Finally, hypercholesterolemic sera from Ldlr-/-Apobec1-/- mice induced fortilin in peritoneal macrophages more robustly than sera from control mice. In conclusion, fortilin, induced in the proatherosclerotic microenvironment in macrophages, protects macrophages against Bax-induced apoptosis, allows them to propagate, and accelerates atherosclerosis. Anti-fortilin therapy thus may represent a promising next generation antiatherosclerotic therapeutic strategy.

KW - Apoptosis

KW - Atherosclerosis

KW - Fortilin

KW - Macrophages

UR - http://www.scopus.com/inward/record.url?scp=84887573073&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887573073&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00570.2013

DO - 10.1152/ajpheart.00570.2013

M3 - Article

C2 - 24043250

AN - SCOPUS:84887573073

VL - 305

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

SN - 0193-1849

IS - 10

ER -