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

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.