Plasminogen regulates pro-opiomelanocortin processing.
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.


OBJECTIVE
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), beta-endorphin and alpha-melanocyte stimulating hormone were elevated after acoustic startle reflex testing in both WT and (Plg-/-) mice. However, in the Plg-/- mice, beta-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, beta-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 beta-endorphin and alpha-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 beta-endorphin and alpha-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 beta-endorphin and alpha-melanocyte stimulating hormone, and interferes with normal brain function.
Wang
N
N
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH 44195, USA.
Zhang
L
L
Miles
L
L
Hoover-Plow
J
J
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism; D000818:Animals; D005341:Fibrinolysin / Q000502:physiology; D006728:Hormones / Q000097:blood / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D009074:Melanocyte-Stimulating Hormones / Q000097:blood / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012022:Reflex, Acoustic; D001615:beta-Endorphin / Q000097:blood / Q000378:metabolism
D006728:Hormones; D012333:RNA, Messenger; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin; D010958:Plasminogen; D000324:Adrenocorticotropic Hormone; D009074:Melanocyte-Stimulating Hormones; D005341:Fibrinolysin