Apolipoprotein mimetic peptides: a new approach for the treatment of asthma

Abstract

New treatments are needed for severe asthmatics to improve disease control and avoid severe toxicities associated with oral corticosteroids. We have used a murine model of house dust mite (HDM)-induced asthma to identify steroid-unresponsive genes that might represent targets for new therapeutic approaches for severe asthma. This strategy identified apolipoprotein E as a steroid-unresponsive gene with increased mRNA expression in the lungs of HDM-challenged mice. Furthermore, apolipoprotein E functioned as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in experimental HDM-induced asthma. The ability of apolipoprotein E, which is expressed by lung macrophages, to attenuate AHR, and goblet cell hyperplasia is mediated by low density lipoprotein (LDL) receptors expressed by airway epithelial cells. Consistent with this, administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130-149 of the LDL receptor-binding domain of the holo-apoE protein, significantly reduced AHR and goblet cell hyperplasia in HDM-challenged apoE(-/-) mice. These findings identified the apolipoprotein E - LDL receptor pathway as a new druggable target for asthma that can be activated by administration of apoE-mimetic peptides. Similarly, apolipoprotein A-I may have therapeutic potential in asthma based upon its anti-inflammatory, anti-oxidative, and anti-fibrotic properties. Furthermore, administration of apolipoprotein A-I mimetic peptides has attenuated airway inflammation, airway remodeling, and airway hyperreactivity in murine models of experimental asthma. Thus, site-directed delivery of inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides may represent novel treatment approaches that can be developed for asthma, including severe disease.

Keywords: apolipoprotein A-I; apolipoprotein A-I mimetic peptide; apolipoprotein E; apolipoprotein E mimetic peptide; asthma.

Figure 1

Structure of apolipoprotein E and apoE-mimetic peptides. Mature holo-apoE is a 299 amino acid protein with polymorphisms at residues 112 and 158 that define the different protein isotypes: apoE2 (cys112, cys158), apoE3 (cys112, arg158), and apoE4 (arg112, arg158). The LDL receptor-binding domain includes residues 130–160. ApoE-mimetic peptides derive from the region including amino acids 130–150 as shown by the filled box. The hatched box extends past the thrombin cleavage site at position 191 to the beginning of the lipid-binding domain at position 215. The amino-terminal portion through residues 1–191 forms a 4-helix anti-parallel bundle followed by a hinge region that extends to residue 215. The carboxy terminal region from 215 to 299 defines the largely unstructured lipid-binding domain with a major lipid-binding region from residues 244 to 272. The apoE-mimetic peptide spanning residues 130–149 is also known as COG130, while the peptide spanning residues 133–149 is also known as COG133.

Figure 2

A proposed model by which endogenous holo-apolipoprotein E (apoE) and exogenously administered apolipoprotein E mimetic peptides [e.g., apoE(130–149)] modulate experimental house dust mite (HDM)-induced asthma (Yao et al., 2010). Both endogenous apoE, which is produced by lung macrophages, and an exogenously administered apoE(130–49) mimetic peptide attenuated airway hyperreactivity and mucous cell metaplasia via an interaction with low density lipoprotein receptors (LDLR), such as those expressed by ciliated airway epithelial cells. Although endogenous apoE did not modulate HDM-induced airway inflammation, administration of the apoE(130–149) mimetic peptide attenuated airway inflammation in apoE knockout mice, but not in LDLR knockout mice, which suggests that the anti-inflammatory effects of the apoE(130–149) mimetic peptide are mediated via a LDLR-dependent mechanism.

Figure 3

5A Apolipoprotein A-I mimetic peptide. The 5A peptide is a 37 amino acid long bihelical peptide, containing a proline that links two amphipathic helices. 5 Alanine substitutions are made in the hydrophobic face of the second helix to reduce its lipid-binding affinity (courtesy of Alexander Andrianov, Ph.D. and adapted with permission from Yao et al., 2011b).

Figure 4

Exogenous administration of the 5A apolipoprotein A-I mimetic peptide attenuates the induction of airway remodeling, airway hyperreactivity, and airway inflammation in a murine model of house dust mite-induced asthma (Yao et al., 2011a).