Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction

Autor: Soeun Ngoy, Felix Kleemiss, Heike Janssen-Peters, Ariana Foinquinos, Angelika Pfanne, Kristian Scherf, Javier Beaumont, Kevin M. Alexander, Arantxa González, Lisa Hobuß, Begoña López, Seema Dangwal, Sudeshna Fisch, Sabine Samolovac, Franziska Kenneweg, Christina Brandenberger, Maria-Teresa Piccoli, Gorka San José, Susana Ravassa, Katharina Schimmel, Lea Grote-Levi, Javier Díez, Mira Jung, Nicola Wilck, Jan Hinrich Braesen, Janet Remke, Karina Zimmer, Robert Geffers, Jan Fiedler, Annette Just, Quoc-Tuan Do, Ke Xiao, Thomas Thum, Katharina Bock, Laura Santer, Sandor Batkai, Volkhard Kaever, Julia Leonardy, Ronglih Liao, Dominik N. Müller, Heike Bähre, Christian Bär, Bradley M. Wertheim, Fabian Philipp Kreutzer, Jessica Schmitz
Přispěvatelé: HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
Cardiac fibrosis
Apoptosis
030204 cardiovascular system & hematology
Ventricular Function
Left
0302 clinical medicine
Fibrosis
Original Research Articles
Medicine
Cells
Cultured
Therapeutic strategy
Extracellular Matrix
Phenanthridines
3. Good health
microRNAs
030220 oncology & carcinogenesis
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING
Cardiology
Cardiomyopathies
Cardiology and Cardiovascular Medicine
medicine.medical_specialty
hypertension
Diastole
03 medical and health sciences
diastole
Selenoprotein P
Physiology (medical)
Internal medicine
Animals
Humans
Cell Proliferation
Rats
Inbred Dahl
business.industry
Myocardium
Natural compound
fibrosis
Cardiovascular Agents
Fibroblasts
medicine.disease
High-Throughput Screening Assays
Bufanolides
Mice
Inbred C57BL
Disease Models
Animal
Cardiovascular and Metabolic Diseases
Heart failure
Amaryllidaceae Alkaloids
Myocardial fibrosis
business
Zdroj: Circulation
United States
Popis: Supplemental Digital Content is available in the text.
Background: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure development, a leading cause of deaths worldwide. Clinically, no therapeutic strategy is available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, our aim was to develop novel antifibrotic therapeutics based on naturally derived substance library screens for the treatment of cardiac fibrosis. Methods: Antifibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts, subsequent validation, and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of human cardiac fibroblasts, modulation of apoptosis, and extracellular matrix expression. In vitro findings were confirmed in vivo with an angiotensin II–mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt-sensitive rat model. To investigate the mechanism underlying the antifibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary human cardiac fibroblasts were analyzed by RNA deep sequencing. Results: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in human cardiac fibroblasts. Using multiple in vitro fibrosis assays and stringent selection algorithms, we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae species) to be effective antifibrotic molecules both in vitro and in vivo, leading to improvement in diastolic function in 2 hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers or the morphology of kidney and liver, providing the first toxicological safety data. Using next-generation sequencing, we identified the conserved microRNA 671-5p and downstream the antifibrotic selenoprotein P1 as common effectors of the antifibrotic compounds. Conclusions: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.
Databáze: OpenAIRE
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