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Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic
Katharina Schimmel1, Mira Jung1, Ariana Foinquinos1
1Institute of Molecular and Translational Therapeutic Strategies (K.S., M.J., A.F., K.B., L.G.-L., K.X., C. Bär, A.P., A.J., K.Z., S.S., H.J.-P., J.R., K.S., S.D., M.-T.P., F.K., F.P.K., F.K., J.L., L.H., L.S., S.B., J.F., T.T.), Hannover Medical School, Germany.
Insights
Researchers identified bufalin and lycorine from natural sources as potential treatments for cardiac fibrosis. These compounds effectively reduced fibrosis in preclinical models, offering hope for new heart failure therapies.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Natural Products Chemistry
Background:
- Myocardial fibrosis is a key factor in cardiac remodeling and heart failure development.
- Current clinical strategies lack specific treatments for maladaptive cardiac fibroblast responses.
- Developing novel antifibrotic therapeutics is crucial for treating heart failure worldwide.
Purpose of the Study:
- To discover and develop novel antifibrotic therapeutics derived from natural compounds.
- To screen a library of natural substances for efficacy against cardiac fibrosis.
- To validate lead compounds through in vitro and in vivo mechanistic studies.
Main Methods:
- Functional screening of 480 natural compounds in human cardiac fibroblasts.
- Assessing antiproliferative effects, apoptosis modulation, and extracellular matrix expression.
- In vivo validation using angiotensin II-mediated murine and Dahl salt-sensitive rat models of cardiac fibrosis.
- RNA deep sequencing to analyze noncoding RNAome changes.
Main Results:
- Identified 15 compounds with antiproliferative effects on cardiac fibroblasts.
- Bufalin (steroid) and lycorine (alkaloid) demonstrated potent in vitro and in vivo antifibrotic activity.
- Improved diastolic function in hypertension-dependent rodent models; showed no toxicity to liver or kidneys.
- Identified conserved microRNA 671-5p and selenoprotein P1 as common downstream effectors.
Conclusions:
- Bufalin and lycorine are promising drug candidates for cardiac fibrosis and diastolic dysfunction.
- These natural compounds offer a potential therapeutic avenue for heart failure treatment.
- Further research into their mechanisms and clinical application is warranted.
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.
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