Collagen‐Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis

Background Cardiac fibrosis is the excessive deposition of extracellular matrix in the heart, triggered by a cardiac insult, aging, genetics, or environmental factors. Molecular imaging of the cardiac extracellular matrix with targeted probes could improve diagnosis and treatment of heart disease. H...

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Autores principales:	Martin Ezeani, Asif Noor, Karen Alt, Sean Lal, Paul S. Donnelly, Christoph E. Hagemeyer, Be’eri Niego
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	cardiomyopathy collagen peptides heart fibrosis molecular imaging molecular probes preclinical imaging Diseases of the circulatory (Cardiovascular) system RC666-701
Acceso en línea:	https://doaj.org/article/1894c8f97e184cbda1ea3d4eb504147f
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spelling	oai:doaj.org-article:1894c8f97e184cbda1ea3d4eb504147f2021-11-23T11:36:35ZCollagen‐Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis10.1161/JAHA.121.0221392047-9980https://doaj.org/article/1894c8f97e184cbda1ea3d4eb504147f2021-09-01T00:00:00Zhttps://www.ahajournals.org/doi/10.1161/JAHA.121.022139https://doaj.org/toc/2047-9980Background Cardiac fibrosis is the excessive deposition of extracellular matrix in the heart, triggered by a cardiac insult, aging, genetics, or environmental factors. Molecular imaging of the cardiac extracellular matrix with targeted probes could improve diagnosis and treatment of heart disease. However, although this technology has been used to demonstrate focal scarring arising from myocardial infarction, its capacity to demonstrate extracellular matrix expansion and diffuse cardiac fibrosis has not been assessed. Methods and Results Here, we report the use of collagen‐targeted peptides labeled with near‐infrared fluorophores for the detection of diffuse cardiac fibrosis in the β2‐AR (β‐2‐adrenergic receptor) overexpressing mouse model and in ischemic human hearts. Two approaches were evaluated, the first based on a T peptide that binds matrix metalloproteinase‐2‐proteolyzed collagen IV, and the second on the cyclic peptide EP‐3533, which targets collagen I. The systemic and cardiac uptakes of both peptides (intravenously administered) were quantified ex vivo by near‐infrared imaging of whole organs, tissue sections, and heart lysates. The peptide accumulation profiles corresponded to an immunohistochemically‐validated increase in collagen types I and IV in hearts of transgenic mice versus littermate controls. The T peptide could encouragingly demonstrate both the intermediate (7 months old) and severe (11 months old) cardiomyopathic phenotypes. Co‐immunostainings of fluorescent peptides and collagens, as well as reduced collagen binding of a control peptide, confirmed the collagen specificity of the tracers. Qualitative analysis of heart samples from patients with ischemic cardiomyopathy compared with nondiseased donors supported the collagen‐enhancement capabilities of these peptides also in the clinical settings. Conclusions Together, these observations demonstrate the feasibility and translation potential of molecular imaging with collagen‐binding peptides for noninvasive imaging of diffuse cardiac fibrosis.Martin EzeaniAsif NoorKaren AltSean LalPaul S. DonnellyChristoph E. HagemeyerBe’eri NiegoWileyarticlecardiomyopathycollagen peptidesheart fibrosismolecular imagingmolecular probespreclinical imagingDiseases of the circulatory (Cardiovascular) systemRC666-701ENJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 10, Iss 18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cardiomyopathy collagen peptides heart fibrosis molecular imaging molecular probes preclinical imaging Diseases of the circulatory (Cardiovascular) system RC666-701
spellingShingle	cardiomyopathy collagen peptides heart fibrosis molecular imaging molecular probes preclinical imaging Diseases of the circulatory (Cardiovascular) system RC666-701 Martin Ezeani Asif Noor Karen Alt Sean Lal Paul S. Donnelly Christoph E. Hagemeyer Be’eri Niego Collagen‐Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis
description	Background Cardiac fibrosis is the excessive deposition of extracellular matrix in the heart, triggered by a cardiac insult, aging, genetics, or environmental factors. Molecular imaging of the cardiac extracellular matrix with targeted probes could improve diagnosis and treatment of heart disease. However, although this technology has been used to demonstrate focal scarring arising from myocardial infarction, its capacity to demonstrate extracellular matrix expansion and diffuse cardiac fibrosis has not been assessed. Methods and Results Here, we report the use of collagen‐targeted peptides labeled with near‐infrared fluorophores for the detection of diffuse cardiac fibrosis in the β2‐AR (β‐2‐adrenergic receptor) overexpressing mouse model and in ischemic human hearts. Two approaches were evaluated, the first based on a T peptide that binds matrix metalloproteinase‐2‐proteolyzed collagen IV, and the second on the cyclic peptide EP‐3533, which targets collagen I. The systemic and cardiac uptakes of both peptides (intravenously administered) were quantified ex vivo by near‐infrared imaging of whole organs, tissue sections, and heart lysates. The peptide accumulation profiles corresponded to an immunohistochemically‐validated increase in collagen types I and IV in hearts of transgenic mice versus littermate controls. The T peptide could encouragingly demonstrate both the intermediate (7 months old) and severe (11 months old) cardiomyopathic phenotypes. Co‐immunostainings of fluorescent peptides and collagens, as well as reduced collagen binding of a control peptide, confirmed the collagen specificity of the tracers. Qualitative analysis of heart samples from patients with ischemic cardiomyopathy compared with nondiseased donors supported the collagen‐enhancement capabilities of these peptides also in the clinical settings. Conclusions Together, these observations demonstrate the feasibility and translation potential of molecular imaging with collagen‐binding peptides for noninvasive imaging of diffuse cardiac fibrosis.
format	article
author	Martin Ezeani Asif Noor Karen Alt Sean Lal Paul S. Donnelly Christoph E. Hagemeyer Be’eri Niego
author_facet	Martin Ezeani Asif Noor Karen Alt Sean Lal Paul S. Donnelly Christoph E. Hagemeyer Be’eri Niego
author_sort	Martin Ezeani
title	Collagen‐Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis
title_short	Collagen‐Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis
title_full	Collagen‐Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis
title_fullStr	Collagen‐Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis
title_full_unstemmed	Collagen‐Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis
title_sort	collagen‐targeted peptides for molecular imaging of diffuse cardiac fibrosis
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/1894c8f97e184cbda1ea3d4eb504147f
work_keys_str_mv	AT martinezeani collagentargetedpeptidesformolecularimagingofdiffusecardiacfibrosis AT asifnoor collagentargetedpeptidesformolecularimagingofdiffusecardiacfibrosis AT karenalt collagentargetedpeptidesformolecularimagingofdiffusecardiacfibrosis AT seanlal collagentargetedpeptidesformolecularimagingofdiffusecardiacfibrosis AT paulsdonnelly collagentargetedpeptidesformolecularimagingofdiffusecardiacfibrosis AT christophehagemeyer collagentargetedpeptidesformolecularimagingofdiffusecardiacfibrosis AT beeriniego collagentargetedpeptidesformolecularimagingofdiffusecardiacfibrosis
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Collagen‐Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis

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