Funktion und therapeutische Eignung des kardial sezernierten Proteins PI16
Final Report Abstract
The myocardium responds to chronic or acute stress in various ways: whereas persistent excessive work demand (as generated by pressure overload) induces cardiac hypertrophy and fibrosis, acute myocardial infarction leads to substantial cell death, scar formation and inflammation. Each of these events involves communication between the cardiac cells and other cell types, and it becomes increasingly evident that secreted factors play important messenger roles therein. We have previously identified Peptidase inhibitor 16 (Pi16) as a secreted cardiac protein which appears in highly enriched in diseased myocardium. Opposed to its potentially misleading name, the function of Pi16 has not been resolved yet. In this funding period, we pursued the hypothesis that Pi16 may be an extracellular signalling protein in the myocardium. To address this experimentally, we had generated Pi16-deficient mice and subjected them to transverse aortic constriction (TAC) as a model for chronic pressure overload. Under these conditions, Pi16 KO mice did not show a phenotype different from their wild-type littermates. 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 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 impairs 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. These findings then prompted us to investigate whether Pi16 may function in acute myocardial disease rather than under chronic stress. For this, we applied myocardial infarction to Pi16-deficient mice and to wildtype mice. This approach revealed that the recovery of heart function from myocardial infarction was significantly improved in Pi16-deficient mice. We then proceeded to investigate the function of Pi16 and provided strong evidence that this protein is involved in the recruitment of immune cells to the myocardium. Hearts from Pi16-deficient mice showed, after myocardial infarction, lower amounts of IL-6 and reduced invasion of granulocytes and neutrophils.
Publications
- Cardiac myocyte-secreted cAMP exerts paracrine action via adenosine receptor activation. J Clin Invest. 2014;124(12):5385-97
Sassi Y, Ahles A, Truong DJ, Baqi Y, Lee SY, Husse B, Hulot JS, Foinquinos A, Thum T, Müller CE, Dendorfer A, Laggerbauer B, Engelhardt S
(See online at https://doi.org/10.1172/JCI74349) - Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium. J Mol Cell Cardiol.
Regn M, Laggerbauer B, Jentzsch C, Ramanujam D, Ahles A, Sichler S, Calzada-Wack J, Koenen R, Braun A, Nieswandt B, Engelhardt S
(See online at https://doi.org/10.1016/j.yjmcc.2016.08.010)
