The overall goal of this grant proposal entitled Fortilin, p53, and atherosclerosis is to define a novel role of fortilin and the fortilin-p53 interaction in atherosclerosis with the intention of establishing anti- fortilin therapy as a viabl strategy against atherosclerosis. By 2025, worldwide death due to atherosclerosis and associated complications is projected to surpass that of every major disease, including cancer, infection, and trauma. The total cost of atherosclerosis-related diseases in the U.S. alone is estimated to be $286 billion annually. After statins, there is no break-through strategy in the pipeline to combat this deadly global disease. Our laboratory has studied fortilin, a 172-amino acid multi-functional protein for the last 15 years. In 2001, we reported for the first time that fortilin protects cells against apoptosis. More recently, we showed that fortilin mediates its anti apoptotic activity through its binding to and inhibition of p53, a tumor suppressor protein. Since (a) p53 protects against not only cancer but also atherosclerosis and (b) fortilin blocks p53, we tested whether the lack of fortilin ameliorated atherosclerosis using Ldlr-/-Apobec1-/- hypercholesterolemic mice, a robust model of atherosclerosis. Strikingly, fortilin+/+Ldlr-/-Apobec1-/- mice had 27 % more atherosclerosis than fortilin+/-Ldlr-/-Apobec1-/- mice with extensive macrophage (M?) infiltration in the atheroma. In addition, immunostaining showed that fortilin is overexpressed in M? and foam cells within human and mouse atherosclerotic lesions. Further, monocytes from patients with coronary atherosclerosis have higher fortilin levels. Finally, we found that hypercholesterolemic sera induce fortilin in M?. Based on these facts, we hypothesize that (a) pro-atherosclerotic milieu induces fortilin in M?, (b) M?-fortilin, when induced, protects M? against p53-induced apoptosis, and (c) unchecked M? proliferate and produce pro- inflammatory cytokines creating a vicious cycle of inflammation and atherosclerogenesis. The facilitative role of M?-fortilin through p53 has never been postulated or tested. To test this overall hypothesis, we propose four Specific Aims.
In Aim 1, we investigate how fortilin is induced in M? and what role induced fortilin plays in M?, using primary and cell line M?.
In Aim 2, we first define the molecular mechanism by which M-fortilin promotes atherosclerogenesis, using M?-specific fortilin knockout (KO) mice on the Ldlr-/- Apobec1-/- genetic background (Aim 2.1.). Next, we examine whether fortilin facilitates atherosclerosis through its inhibition of p53, by creating M?-specific fortilin KO mice on the p53-/-Ldlr-/-Apobec1-/- genetic background (Aim 2.2.).
In Aim 3, we expect to show that M?-specific fortilin silencing re-activates p53 and protects against atherosclerosis by orally administering ?1,3-D-glucan-encapsulated (GeRP) fortilin siRNA particles to Ldlr-/- Apobec1-/- mice. At the end of the project, we expect M?-specific anti-fortilin therapy to be found to be a ground-breaking strategy against the deadly and global disease of atherosclerosis.
Although the world-wide death rate due to atherosclerosis and its complications will soon surpass that of every major disease, including cancer, infection, and trauma, we have no promising therapy currently in the pipeline after statins. Based on our ground-breaking discovery that fortilin facilitates atherosclerosis by protecting macrophages against apoptosis, we are proposing to establish fortilin as a novel molecular target of atherosclerosis therapy.
|Pinkaew, Decha; Chattopadhyay, Abhijnan; King, Matthew D et al. (2017) Fortilin binds IRE1? and prevents ER stress from signaling apoptotic cell death. Nat Commun 8:18|
|Chattopadhyay, Abhijnan; Pinkaew, Decha; Doan, Hung Q et al. (2016) Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice. Sci Rep 6:18701|
|Sinthujaroen, Patuma; Wanachottrakul, Nattaporn; Pinkaew, Decha et al. (2014) Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo. BBA Clin 2:103-111|
|Pinkaew, Decha; Le, Rachel J; Chen, Yanjie et al. (2013) Fortilin reduces apoptosis in macrophages and promotes atherosclerosis. Am J Physiol Heart Circ Physiol 305:H1519-29|