A ROS-Responsive Dual-Functional H₂S Donor for Synergistic Cardioprotection

Area of Science:

• Biomedical Engineering
• Cardiovascular Research
• Drug Delivery Systems

Background:

• Myocardial ischemia/reperfusion injury (MIRI) poses significant therapeutic challenges.
• Existing hydrogen sulfide (H₂S) donors lack targeted delivery and efficient molecular design.
• Reactive oxygen species (ROS) are key mediators in MIRI pathology.

Purpose of the Study:

• To develop novel ROS-responsive dual-functional H₂S donors for MIRI treatment.
• To investigate the synergistic therapeutic effects of codelivering H₂S and a β-carboline derivative.
• To evaluate the efficacy of the lead compound (7j) in cellular and animal models of MIRI.

Main Methods:

• Conjugation of a β-carboline with an H₂O₂-cleavable arylboronate H₂S donor.
• In vitro assessment in H9c2 cardiomyoblasts and HUVECs under oxidative stress.
• In vivo evaluation using a rat MIRI model to determine infarct size reduction.

Main Results:

• The lead donor (7j) demonstrated H₂O₂-triggered release of H₂S and the active β-carboline (5j).
• Compound 7j mitigated oxidative stress, suppressed apoptosis, preserved mitochondrial function, and enhanced antioxidant enzyme activity in vitro.
• In vivo, 7j significantly reduced myocardial infarct size in a rat MIRI model.

Conclusions:

• A synergistic molecular strategy was established for targeted MIRI therapy.
• Leveraging the pathological ROS microenvironment enables efficient codelivery of therapeutic agents.
• This approach offers a promising therapeutic avenue for myocardial ischemia/reperfusion injury.