Research Article: The heparin-binding proteome in normal pancreas and murine experimental acute pancreatitis

Date Published: June 18, 2019

Publisher: Public Library of Science

Author(s): Quentin M. Nunes, Dunhao Su, Philip J. Brownridge, Deborah M. Simpson, Changye Sun, Yong Li, Thao P. Bui, Xiaoying Zhang, Wei Huang, Daniel J. Rigden, Robert J. Beynon, Robert Sutton, David G. Fernig, Jon M. Jacobs.


Acute pancreatitis (AP) is acute inflammation of the pancreas, mainly caused by gallstones and alcohol, driven by changes in communication between cells. Heparin-binding proteins (HBPs) play a central role in health and diseases. Therefore, we used heparin affinity proteomics to identify extracellular HBPs in pancreas and plasma of normal mice and in a caerulein mouse model of AP. Many new extracellular HBPs (360) were discovered in the pancreas, taking the total number of HBPs known to 786. Extracellular pancreas HBPs form highly interconnected protein-protein interaction networks in both normal pancreas (NP) and AP. Thus, HBPs represent an important set of extracellular proteins with significant regulatory potential in the pancreas. HBPs in NP are associated with biological functions such as molecular transport and cellular movement that underlie pancreatic homeostasis. However, in AP HBPs are associated with additional inflammatory processes such as acute phase response signalling, complement activation and mitochondrial dysfunction, which has a central role in the development of AP. Plasma HBPs in AP included known AP biomarkers such as serum amyloid A, as well as emerging targets such as histone H2A. Other HBPs such as alpha 2-HS glycoprotein (AHSG) and histidine-rich glycoprotein (HRG) need further investigation for potential applications in the management of AP. Pancreas HBPs are extracellular and so easily accessible and are potential drug targets in AP, whereas plasma HBPs represent potential biomarkers for AP. Thus, their identification paves the way to determine which HBPs may have potential applications in the management of AP.

Partial Text

The pancreas develops from endodermal cells in the foregut and has important exocrine and endocrine functions [1]. Acute pancreatitis (AP) is acute inflammation of the pancreas and is mainly caused by gallstones and alcohol [2]. It is a leading gastrointestinal cause of hospitalization and has significant quality of life implications for the patient and cost implications for health systems [3]. Although most episodes of AP are mild and self-limiting, the severe form of the disease, accompanied by a systemic inflammatory response syndrome and multi-organ failure, is associated with a high mortality. At a cellular level disruption of calcium signaling and mitochondrial dysfunction have been implicated in the pathogenesis of AP [4, 5].

HBPs are functionally associated with the regulation of cell communication that underlies many physiological and pathological processes. AP represents a disease with unmet clinical need from the perspective of prognosis and treatment, particularly with respect to progression to severe AP, which can be life-threatening. Encouraged by the initial work using mRNA as a proxy for pancreas HBPs [13], we, therefore, determined whether there were changes in the levels of HBPs associated with AP in the murine caerulein model of the disease. One focus was on extracellular HBPs of the pancreas itself. Only extracellular HBPs were considered, because, whilst there is clear evidence for intracellular HS [42–44], there is no means at present to distinguish in a proteomic experiment intracellular proteins that interact with intracellular HS from those that natively interact solely with another intracellular polyanion, such as phosphorylated lipids and nucleic acids. The present analysis aimed to identify disease-related HBPs, and so processes, some of which may be potential therapeutic targets. However, potential biomarkers need to be more accessible, as sampling the pancreas is invasive, so plasma HBPs were also analysed. In this instance, because plasma is by definition cell-free, potentially intracellular proteins were also of interest. Moreover, the presence of exosome-associated proteins (S3, S4, S11 & S12 Tables) is consistent with at least a subset of these vesicles binding heparin [45–47].




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