Reproducing extracellular matrix adverse remodelling of non-ST myocardial infarction in a large animal model

Paolo Contessotto, Renza Spelat, Federico Ferro, Vaidas Vysockas, Aušra Krivickienė, Chunsheng Jin, Sandrine Chantepie, Clizia Chinello, Audrys G. Pauza, Camilla Valente, Mindaugas Rackauskas, Alvise Casara, Vilma Zigmantaitė, Fulvio Magni, Dulce Papy-Garcia, Niclas G. Karlsson, Eglė Ereminienė, Abhay Pandit () and Mark Da Costa ()
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Paolo Contessotto: University of Galway
Renza Spelat: University of Galway
Federico Ferro: University of Galway
Vaidas Vysockas: Lithuanian University of Health Sciences
Aušra Krivickienė: Lithuanian University of Health Sciences
Chunsheng Jin: University of Gothenburg
Sandrine Chantepie: University Paris Est Créteil
Clizia Chinello: University of Milano-Bicocca
Audrys G. Pauza: Lithuanian University of Health Sciences
Camilla Valente: University of Padova
Mindaugas Rackauskas: UF Health Heart and Vascular Hospital
Alvise Casara: University of Padova
Vilma Zigmantaitė: Lithuanian University of Health Sciences
Fulvio Magni: University of Milano-Bicocca
Dulce Papy-Garcia: University Paris Est Créteil
Niclas G. Karlsson: University of Gothenburg
Eglė Ereminienė: Lithuanian University of Health Sciences
Abhay Pandit: University of Galway
Mark Da Costa: University of Galway

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract The rising incidence of non-ST-segment elevation myocardial infarction (NSTEMI) and associated long-term high mortality constitutes an urgent clinical issue. Unfortunately, the study of possible interventions to treat this pathology lacks a reproducible pre-clinical model. Indeed, currently adopted small and large animal models of MI mimic only full-thickness, ST-segment-elevation (STEMI) infarcts, and hence cater only for an investigation into therapeutics and interventions directed at this subset of MI. Thus, we develop an ovine model of NSTEMI by ligating the myocardial muscle at precise intervals parallel to the left anterior descending coronary artery. Upon histological and functional investigation to validate the proposed model and comparison with STEMI full ligation model, RNA-seq and proteomics show the distinctive features of post-NSTEMI tissue remodelling. Transcriptome and proteome-derived pathway analyses at acute (7 days) and late (28 days) post-NSTEMI pinpoint specific alterations in cardiac post-ischaemic extracellular matrix. Together with the rise of well-known markers of inflammation and fibrosis, NSTEMI ischaemic regions show distinctive patterns of complex galactosylated and sialylated N-glycans in cellular membranes and extracellular matrix. Identifying such changes in molecular moieties accessible to infusible and intra-myocardial injectable drugs sheds light on developing targeted pharmacological solutions to contrast adverse fibrotic remodelling.

Date: 2023
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DOI: 10.1038/s41467-023-36350-1

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