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 fortilin-deficient ( 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.

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…Ken Fujise's group has generated a mouse model with heterozygous deficiency of TCTP/fortilin in a background of hypercholesterolemia, which develops atherosclerotic characteristics, similar to those in humans (Pinkaew et al 2013). Studying this animal model, they arrived at the conclusion that TCTP/fortilin acts by reducing apoptosis in macrophages, one of the main players in the development of atherosclerosis.…”

Fortilin: A Potential Target for the Prevention and Treatment of Human Diseases

“…In both the aorta of these mice and human atherosclerotic tissue samples obtained from carotid endarterectomy, fortilin TCTP was found to be abundantly expressed in the atherosclerotic intima, and its expression was positively correlated with the degree of atherosclerosis and temporospatially coincided with MΦs and FCs [23]. To test the hypothesis that fortilin TCTP facilitates atherosclerosis, we generated fortilin TCTP+/+ Ldlr −/− Apobec1 −/− and fortilin TCTP+/− Ldlr −/− Apobec1 −/− mice.…”

“…ApoE deficiency was also shown to result in defective phagocytosis of apoptotic cells and increased inflammation [76]. After placing Ldlr −/− Apobec1 −/− mice on normal chow for 10 months, we found that fortilin TCTP deficiency (fortilin TCTP+/− compared with fortilin TCTP+/+ ) reduced atherosclerosis by 27% [23]. There was no difference in body weight, blood pressure, or lipid profile between fortilin TCTP+/+ Ldlr −/− Apobec1 −/− and fortilin TCTP+/− Ldlr −/− Apobec1 −/− mice.…”

“…There was no difference in body weight, blood pressure, or lipid profile between fortilin TCTP+/+ Ldlr −/− Apobec1 −/− and fortilin TCTP+/− Ldlr −/− Apobec1 −/− mice. This relatively modest decrease in atherosclerosis in these mice was due to the moderate reduction of tissue fortilin TCTP levels (28–30%) secondary to fortilin TCTP heterozygosity (fortilin TCTP+/− ) [23]. Mechanistically, the atherosclerotic lesions of fortilin TCTP+/− Ldlr −/− Apobec1 −/− mice contained fewer MΦ and more apoptotic cells than those of fortilin TCTP+/+ Ldlr −/− Apobec1 −/− mice, as shown by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and flow cytometry analysis [23].…”

“…This relatively modest decrease in atherosclerosis in these mice was due to the moderate reduction of tissue fortilin TCTP levels (28–30%) secondary to fortilin TCTP heterozygosity (fortilin TCTP+/− ) [23]. Mechanistically, the atherosclerotic lesions of fortilin TCTP+/− Ldlr −/− Apobec1 −/− mice contained fewer MΦ and more apoptotic cells than those of fortilin TCTP+/+ Ldlr −/− Apobec1 −/− mice, as shown by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and flow cytometry analysis [23]. Intriguingly, there was no difference in the number of VSMCs between the two mouse strains, indicating that constitutional deficiency of fortilin TCTP led specifically to a reduction in MΦs and not VSMCs [23].…”