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| Item Type: | Article |
|---|---|
| Title: | Natural compound library screening identifies new molecules for the treatment of cardiac fibrosis and diastolic dysfunction |
| Creators Name: | Schimmel, K., Jung, M., Foinquinos, A., San José, G., Beaumont, J., Bock, K., Grote-Levi, L., Xiao, K., Bär, C., Pfanne, A., Just, A., Zimmer, K., Ngoy, S., López, B., Ravassa, S., Samolovac, S., Janssen-Peters, H., Remke, J., Scherf, K., Dangwal, S., Piccoli, M.T., Kleemiss, F., Kreutzer, F.P., Kenneweg, F., Leonardy, J., Hobuß, L., Santer, L., Do, Q.T., Geffers, R., Braesen, J.H., Schmitz, J., Brandenberger, C., Müller, D.N., Wilck, N., Kaever, V., Bähre, H., Batkai, S., Fiedler, J., Alexander, K.M., Wertheim, B.M., Fisch, S., Liao, R., Diez, J., González, A. and Thum, T. |
| Abstract: | BACKGROUND: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure (HF) development, a leading cause of deaths worldwide. Clinically there is no therapeutic strategy available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, we aimed at the development of novel anti-fibrotic therapeutics based on natural-derived substance library screens for the treatment of cardiac fibrosis. METHODS: Anti-fibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts (HCFs), subsequent validation and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of HCFs, for modulation of apoptosis and extracellular matrix expression. In vitro findings were confirmed in vivo, using an angiotensin II (Ang 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 anti-fibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary HCFs were analyzed by RNA-deep sequencing. RESULTS: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in HCFs. 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 anti-fibrotic molecules both in vitro and in vivo leading to improvement in diastolic function in two hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers nor the morphology of kidney and liver, providing first toxicological safety data. By next-generation sequencing we identified the conserved microRNA (miR) miR-671-5p and downstream the antifibrotic selenoprotein P1 (SEPP1) as common effectors of the anti-fibrotic compounds. CONCLUSION: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction. |
| Keywords: | Diastole, Fibrosis, Hypertension, microRNAs, Animals, Mice, Rats |
| Source: | Circulation |
| ISSN: | 0009-7322 |
| Publisher: | American Heart Association |
| Volume: | 141 |
| Number: | 9 |
| Page Range: | 751-767 |
| Date: | 3 March 2020 |
| Official Publication: | https://doi.org/10.1161/CIRCULATIONAHA.119.042559 |
| PubMed: | View item in PubMed |
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