Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation
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Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation. / Barallobre-Barreiro, Javier; Gupta, Shashi K; Zoccarato, Anna; Kitazume-Taneike, Rika; Fava, Marika; Yin, Xiaoke; Werner, Tessa; Hirt, Marc N; Zampetaki, Anna; Viviano, Alessandro; Chong, Mei; Bern, Marshall; Kourliouros, Antonios; Domenech, Nieves; Willeit, Peter; Shah, Ajay M; Jahangiri, Marjan; Schaefer, Liliana; Fischer, Jens W; Iozzo, Renato V; Viner, Rosa; Thum, Thomas; Heineke, Joerg; Kichler, Antoine; Otsu, Kinya; Mayr, Manuel.
in: CIRCULATION, Jahrgang 134, Nr. 11, 13.09.2016, S. 817-32.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation
AU - Barallobre-Barreiro, Javier
AU - Gupta, Shashi K
AU - Zoccarato, Anna
AU - Kitazume-Taneike, Rika
AU - Fava, Marika
AU - Yin, Xiaoke
AU - Werner, Tessa
AU - Hirt, Marc N
AU - Zampetaki, Anna
AU - Viviano, Alessandro
AU - Chong, Mei
AU - Bern, Marshall
AU - Kourliouros, Antonios
AU - Domenech, Nieves
AU - Willeit, Peter
AU - Shah, Ajay M
AU - Jahangiri, Marjan
AU - Schaefer, Liliana
AU - Fischer, Jens W
AU - Iozzo, Renato V
AU - Viner, Rosa
AU - Thum, Thomas
AU - Heineke, Joerg
AU - Kichler, Antoine
AU - Otsu, Kinya
AU - Mayr, Manuel
N1 - © 2016 American Heart Association, Inc.
PY - 2016/9/13
Y1 - 2016/9/13
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1161/CIRCULATIONAHA.115.016423
DO - 10.1161/CIRCULATIONAHA.115.016423
M3 - SCORING: Journal article
C2 - 27559042
VL - 134
SP - 817
EP - 832
JO - CIRCULATION
JF - CIRCULATION
SN - 0009-7322
IS - 11
ER -
