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Glycoproteomics Reveals Decorin Peptides with Anti-Myostatin Activity in Human Atrial Fibrillation

Research output: Contribution to journalArticle

Javier Barallobre-Barreiro, Shashi K. Gupta, Anna Zoccarato, Rika Kitazume-Taneike, Marika Fava, Xiaoke Yin, Tessa Werner, Marc N. Hirt, Anna Zampetaki, Alessandro Viviano, Mei Chong, Marshall Bern, Antonios Kourliouros, Nieves Domenech, Peter Willeit, Ajay M. Shah, Marjan Jahangiri, Liliana Schaefer, Jens W. Fischer, Renato V. Iozzo & 6 more Rosa Viner, Thomas Thum, Joerg Heineke, Antoine Kichler, Kinya Otsu, Manuel Mayr

Original languageEnglish
Pages (from-to)817-832
Number of pages16
JournalCirculation (Baltimore)
Volume134
Issue number11
Early online date24 Aug 2016
DOIs
Publication statusPublished - 13 Sep 2016

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Abstract

Background: Myocardial fibrosis is a feature of many cardiac diseases. We used proteomics to profile glycoproteins in the human cardiac extracellular matrix (ECM). Methods: Atrial specimens were analyzed by mass spectrometry after extraction of ECM proteins and enrichment for glycoproteins or glycopeptides. Results: ECM-related glycoproteins were identified in left and right atrial appendages from the same patients. Several known glycosylation sites were confirmed. In addition, putative and novel glycosylation sites were detected. On enrichment for glycoproteins, peptides of the small leucine-rich proteoglycan decorin were identified consistently in the flowthrough. Of all ECM proteins identified, decorin was found to be the most fragmented. Within its protein core, 18 different cleavage sites were identified. In contrast, less cleavage was observed for biglycan, the most closely related proteoglycan. Decorin processing differed between human ventricles and atria and was altered in disease. The C-terminus of decorin, important for the interaction with connective tissue growth factor, was detected predominantly in ventricles in comparison with atria. In contrast, atrial appendages from patients in persistent atrial fibrillation had greater levels of full-length decorin but also harbored a cleavage site that was not found in atrial appendages from patients in sinus rhythm. This cleavage site preceded the N-terminal domain of decorin that controls muscle growth by altering the binding capacity for myostatin. Myostatin expression was decreased in atrial appendages of patients with persistent atrial fibrillation and hearts of decorin null mice. A synthetic peptide corresponding to this decorin region dose-dependently inhibited the response to myostatin in cardiomyocytes and in perfused mouse hearts. Conclusions: This proteomics study is the first to analyze the human cardiac ECM. Novel processed forms of decorin protein core, uncovered in human atrial appendages, can regulate the local bioavailability of antihypertrophic and profibrotic growth factors.

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