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J Mol Cell Cardiol. 2016 Oct;99:57-64. doi: 10.1016/j.yjmcc.2016.08.010. Epub 2016 Aug 15.

Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium.

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Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
Institute of Pathology, Helmholtz Center Munich, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider Straße 2, 97080 Würzburg, Germany.
Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany; DZHK (German Center for Cardiovascular Research) partner site Munich Heart Alliance, 80802 Munich, Germany. Electronic address:


A key response of the myocardium to stress is the secretion of factors with paracrine or endocrine function. Intriguing in this respect is peptidase inhibitor 16 (PI16), a member of the CAP family of proteins which we found to be highly upregulated in cardiac disease. Up to this point, the mechanism of action and physiological function of PI16 remained elusive. Here, we show that PI16 is predominantly expressed by cardiac fibroblasts, which expose PI16 to the interstitium via a glycophosphatidylinositol (-GPI) membrane anchor. Based on a reported genetic association of PI16 and plasma levels of the chemokine chemerin, we investigated whether PI16 regulates post-translational processing of its precursor pro-chemerin. PI16-deficient mice were engineered and found to generate higher levels of processed chemerin than wildtype mice. Purified recombinant PI16 efficiently inhibited cathepsin K, a chemerin-activating protease, in vitro. Moreover, we show that conditioned medium from PI16-overexpressing cells impaired the activation of pro-chemerin. Together, our data indicate that PI16 suppresses chemerin activation in the myocardium and suggest that this circuit may be part of the cardiac stress response.


Chemerin; Chemerin processing; Peptidase inhibitor 16 (PI16); Protease inhibition; RARRES2; TIG2

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