Comparison of various iron chelators and prochelators as protective agents against cardiomyocyte oxidative injury

Area of Science:

• Biochemistry
• Cardiovascular Medicine
• Pharmacology

Background:

• Oxidative stress is central to cardiovascular disorders, with free iron exacerbating damage via toxic hydroxyl radical formation.
• Traditional iron chelators risk toxicity in non-iron overload conditions, necessitating advanced strategies like prochelators activated by oxidative stress.

Purpose of the Study:

• To evaluate novel boronate-masked prochelator analogs for their efficacy and safety in protecting cardiac cells from oxidative injury.
• To identify a prochelator with superior cytoprotective properties and reduced inherent toxicity compared to existing chelators.

Main Methods:

• Assessed cell-membrane-permeable iron chelators (deferasirox, SIH, HAPI) and five prochelator analogs against hydrogen peroxide-induced oxidative injury in cardiac cells.
• Compared protective efficiency and cytotoxicity of prochelators (BHAPI, BSIH-PD) and their parent chelators (HAPI, SIH).
• Investigated the most promising prochelator, BSIH, for its effects on mitochondrial and lysosomal function and cell death in H9c2 cells and primary cardiomyocytes.

Main Results:

• Deferasirox-derived agents TIP and TRA-IMM showed minimal protection and significant toxicity.
• Aroylhydrazone prochelators BHAPI and BSIH-PD provided substantial cytoprotection with lower toxicity than parent compounds.
• BSIH demonstrated excellent protective effects against oxidative stress-induced cell damage and dysfunction, with no observed toxicity up to 600 μM over 72 hours.

Conclusions:

• The aroylhydrazone prochelator BSIH exhibits superior cytoprotective efficacy and safety profiles.
• BSIH effectively safeguards cardiac cells from oxidative damage, including mitochondrial and lysosomal impairment.
• BSIH warrants further investigation as a potential therapeutic agent for cardiovascular diseases involving oxidative stress.