Hemoglobin-derived peptides as novel type of bioactive signaling molecules

Abstract

Most bioactive peptides are generated by proteolytic cleavage of large precursor proteins followed by storage in secretory vesicles from where they are released upon cell stimulation. Examples of such bioactive peptides include peptide neurotransmitters, classical neuropeptides, and peptide hormones. In the last decade, it has become apparent that the breakdown of cytosolic proteins can generate peptides that have biological activity. A case in point and the focus of this review are hemoglobin-derived peptides. In vertebrates, hemoglobin (Hb) consists of a tetramer of two α- and two β-globin chains each containing a prosthetic heme group, and is primarily involved in oxygen delivery to tissues and in redox reactions (Schechter Blood 112:3927-3938, 2008). The presence of α- and/or β-globin chain in tissues besides red blood cells including rodent and human brain and peripheral tissues (Liu et al. Proc Natl Acad Sci USA 96:6643-6647, 1999; Newton et al. J Biol Chem 281:5668-5676, 2006; Wride et al. Mol Vis 9:360-396, 2003; Setton-Avruj Exp Neurol 203:568-578, 2007; Ohyagi et al. Brain Res 635:323-327, 1994; Schelshorn et al. J Cereb Blood Flow Metab 29:585-595, 2009; Richter et al. J Comp Neurol 515:538-547, 2009) suggests that globins and/or derived peptidic fragments might play additional physiological functions in different tissues. In support of this hypothesis, a number of Hb-derived peptides have been identified and shown to have diverse functions (Ivanov et al. Biopoly 43:171-188, 1997; Karelin et al. Neurochem Res 24:1117-1124, 1999). Modern mass spectrometric analyses have helped in the identification of additional Hb peptides (Newton et al. J Biol Chem 281:5668-5676, 2006; Setton-Avruj Exp Neurol 203:568-578, 2007; Gomes et al. FASEB J 23:3020-3029, 2009); the molecular targets for these are only recently beginning to be revealed. Here, we review the status of the Hb peptide field and highlight recent reports on the identification of a molecular target for a novel set of Hb peptides, hemopressins, and the implication of these peptides to normal cell function and disease. The potential therapeutic applications for these Hb-derived hemopressin peptides will also be discussed.

Fig. 1

Schematic showing positions in Hbα and Hbβ chains of the various bioactive peptides described in this review. Hb hemoglobin, Hp hemopressin

Fig. 2

Comparison of the amount of Hp and Angiotensin II present in 2 kDa dialysis bags. 1 ml Hp a or angiotensin II b solution (0.1 or 0.5 mg/ml) was placed in a dialysis bag of 2 kDa cutoff (Slide-A-Lyzer Dialysis Cassettes, Pierce) and subjected to dialysis against PBS for 24 h. Aliquots (20 μl) of the 24 h dialysate were subjected to HPLC analysis. The amount of Hp or angiotensin II in the bag before and after dialysis was calculated from the area under the curve and from a standard curved obtained by HPLC analysis of Hp or angiotensin II (0-0.5 mg/ml). There was <5% peptide associated with the dialysis cassette itself. a The area under the curve for Hp (0.5 mg/ml) before dialysis was 15758985 and after 24 h dialysis was 7014526. b The area under the curve for angiotensin II (0.5 mg/ml) before dialysis was 10389021 and after 24 h dialysis was 1490275. Insets in a and b show the amount of hemopressin or angiotensin II peptide in the dialysis bag before and 24 h after dialysis. Data shows that compared to angiotensin II more Hp is retained in the dialysis bag suggesting that there is increased aggregation of Hp. Data is the mean ± SE of three experiments