Abstract
Equine pituitary pars intermedia dysfunction (PPID) is characterized by hyperplasia of the pars intermedia (PI) melanotrophs of the pituitary gland (PG), and increased production of proopiomelanocortin (POMC). POMC is cleaved by prohormone convertase 1 (PC1) to produce adrenocorticotropic hormone (ACTH), and further processing of ACTH by PC2 to produce alpha-melanocyte stimulating hormone (α-MSH) and corticotropin-like intermediate peptide (CLIP). High plasma ACTH concentrations in horses with PPID might be related to reduced conversion of ACTH to α-MSH by PCs. The hypothesis of this study was that PC1 and PC2 expression in the pituitary gland are altered in PPID, resulting in an abnormal relative abundance of POMC derived proteins. The objectives of this study were to identify the partial sequences of equine POMC, PC1, and PC2 mRNAs; and to determine whether the expression of POMC, PC1, and PC2 mRNAs in whole pituitary extracts, and POMC-protein in the cavernous sinus blood of horses are altered in PPID. We confirmed (RT-PCR and sequencing) that the partial sequences obtained match the corresponding regions of predicted equine POMC, PC1 and PC2 sequences. The expression (quantification by RT-qPCR) of POMC, PC1 and PC2 mRNAs were found upregulated in the pituitary of horses with PPID. Plasma (measured using RIA/ELISA) ACTH and α-MSH were elevated in PPID horses. These results indicate distinct differences in gene and protein expression of POMC and its intermediates, and processing enzymes in PPID. It provides evidence to support the notion that local, pituitary-specific inadequacies in prohormone processing likely contribute to equine PPID.
Highlights
Equine pituitary pars intermedia dysfunction (PPID), known as equine Cushing’s disease, is a common disease of horses older than 15 years
Our research presented here provides three sets of novel information in equine endocrinology
Within the sequences confirmed here, there are no key differences in the amino acid sequence of hormones encoded in POMC, or prohormone convertase 1 (PC1) and PC2 between normal and PPID horses
Summary
Equine pituitary pars intermedia dysfunction (PPID), known as equine Cushing’s disease, is a common disease of horses older than 15 years. In mice with dopamine type-2 (D2R) receptor deficiencies, the gene expression of proopiomelanocortin (POMC) and its associated prohormone convertases (PC1 and PC2) are upregulated [6] This results in an overabundance of downstream POMC-peptides, such as adrenocorticotrophic hormone (ACTH) cleaved from POMC by PC1; and alpha-melanocyte stimulating hormone (α-MSH) and corticotrophin-like immune peptide (CLIP) cleaved from ACTH by PC2, being released into the systemic circulation. This theory is given additional support by the fact that clinical signs and endogenous ACTH levels normalize in the face of treatment with a dopamine agonist [7]
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