Cardiac fibrosis inhibitor CTPR390 prevents structural and morphological changes in human engineered cardiac connective tissue
David Maestro,
Ana Palanca,
Helena Soto,
I. Llarena,
Alisa Nicole DeGrave,
Gabriela Guedes,
Guilherme Henrique de Oliveira,
André Luiz Coelho Conceição,
Verónica Mieites,
Jose M. Icardo,
Carlos Sanchez-Cano,
Olga M. Conde,
Susanne Lutz,
Aitziber L. Cortajarena,
Ana V. Villar
Affiliations
David Maestro
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria (UC), Santander, Spain
Ana Palanca
Departamento de Anatomía y Biología Celular, Universidad de Cantabria, Santander, Spain
Helena Soto
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria (UC), Santander, Spain; Valdecilla Biomedical Research Institute (IDIVAL), 39011 Santander, Spain
I. Llarena
Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 194, 20014 Donostia-San Sebastián, Spain
Alisa Nicole DeGrave
Institute of Pharmacology and Toxicology, University Medical Center, Goettingen, Germany; DZHK (German Centre for Cardiovascular Research) Partner Site, Goettingen, Germany
Gabriela Guedes
Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 194, 20014 Donostia-San Sebastián, Spain
Guilherme Henrique de Oliveira
Donostia International Physics Center, Manuel Lardizabal Ibilbidea 4, 20018 Donostia, Spain
Photonics Engineering Group, University of Cantabria, 39005 Santander, Spain; Valdecilla Biomedical Research Institute (IDIVAL), 39011 Santander, Spain
Jose M. Icardo
Departamento de Anatomía y Biología Celular, Universidad de Cantabria, Santander, Spain
Carlos Sanchez-Cano
Donostia International Physics Center, Manuel Lardizabal Ibilbidea 4, 20018 Donostia, Spain; Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain; Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, Euskal Herriko Unibertsitatea UPV/EHU, 20018 Donostia-San Sebastian, Spain
Olga M. Conde
Photonics Engineering Group, University of Cantabria, 39005 Santander, Spain; Valdecilla Biomedical Research Institute (IDIVAL), 39011 Santander, Spain; CIBER-BBN, Biomedical Research Networking Center—Bioengineering, Biomaterials, and Nanomedicine, Avda. Monforte de Lemos 3–5, Pabellón 11, Planta 0, 28029 Madrid, Spain
Susanne Lutz
Institute of Pharmacology and Toxicology, University Medical Center, Goettingen, Germany; DZHK (German Centre for Cardiovascular Research) Partner Site, Goettingen, Germany
Aitziber L. Cortajarena
Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 194, 20014 Donostia-San Sebastián, Spain; Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea, Euskal Herriko Unibertsitatea UPV/EHU, 20018 Donostia-San Sebastian, Spain
Ana V. Villar
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria (UC), Santander, Spain; Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Santander, Spain; Corresponding author
Summary: Cardiac fibrosis is a key characteristic of heart failure. CTPR390, an experimental anti-fibrotic inhibitor targeting Hsp90, has shown success in animal models, but remains unexplored in human cardiac models. This study evaluated an engineered cardiac connective tissue (ECCT) model, focusing on changes in the extracellular matrix and fibroblasts. Results showed that CTPR390 prevented architectural changes in TGFβ1-activated ECCT, preserving tissue perimeter, collagen fibers alignment while reducing structured areas and degree of collagen structuration. CTPR390 treatment reduced cell area of fibroblasts under tension, without changes in the internal rounded cells devoid of tension. Fibroblast recruitment to tension areas was diminished, showing biomechanical behavior similar to control ECCT. This treatment also lowered the gene and protein expression of key pro-fibrotic markers. Here, advanced biotechnology was employed to detect the detailed structure of tissue fibrosis reduction after administering CTPR390, representing a significant advancement toward clinical application for cardiac fibrosis treatment.
