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 language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 305 |
| Issue number | 10 |
| DOIs | |
| State | Published - Nov 15 2013 |
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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 journal › Article
}
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
VL - 305
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
SN - 0193-1849
IS - 10
ER -