Plasminogen regulates pro-opiomelanocortin processing

Abstract

Background: Plasminogen-deficient mice exhibit behavioral differences in response to stress, including a markedly reduced acoustic startle reflex response compared with wild-type (WT) littermates. The acoustic startle reflex activates the hypothalamic-pituitary axis and is modulated by these hormones. Objectives: The purpose of this study was to investigate whether plasminogen plays a role in the processing of hormones in the hypothalamic-pituitary axis. Methods: In this study the concentration of plasma, pituitary, and brain hypothalamic-pituitary axis hormones and precursor processing was examined in WT and plasminogen deficient (Plg-/-) mice before and after acoustic startle reflex testing. Results: Plasma adrenocorticotropic hormone (ACTH), β-endorphin and α-melanocyte stimulating hormone were elevated after acoustic startle reflex testing in both WT and (Plg-/-) mice. However, in the Plg-/-mice, β-endorphin values were 43, 35, and 45% lower in the plasma, pituitary, and whole brain, respectively, compared with the WT mice. Plasmin readily degraded precursor peptides, the 23-kDa precursor, β-lipotropin, and ACTH, when presented as purified proteins or as the secretory products of mouse pituitary cells (AtT-20). The precursor peptide, 23 kDa, for β-endorphin and α-melanocyte stimulating hormone was reduced in the pituitaries from the Plg-/- mice, and the mRNA for Plg was found in pituitaries from WT mice. Infusion of β -endorphin and α-melanocyte stimulating hormone into the brain of Plg-/-mice increased acoustic startle reflex. Conclusions: The results of this study show that plasmin is involved in the processing of hormones derived from the pro-opiomelanocortin precursor in the intermediate pituitary. A deficiency of plasminogen reduces processing of β-endorphin and α-melanocyte stimulating hormone, and interferes with normal brain function. © 2004 International Society on Thrombosis and Haemostasis.