Vasorelaxant Activity of AP39, a Mitochondria-Targeted H₂S Donor, on Mouse Mesenteric Artery Rings In Vitro

Area of Science:

• Biomedical science
• Cardiovascular research
• Mitochondrial medicine

Background:

• Mitochondria-targeted hydrogen sulfide (H2S) donors, such as AP39, offer therapeutic benefits for cardiovascular conditions like diabetes and hypertension.
• Direct vascular effects and mechanisms of H2S donors remain largely uninvestigated.

Purpose of the Study:

• To investigate the in vitro vascular effects and elucidate the mechanisms of action of AP39 on mouse mesenteric arteries.

Main Methods:

• Analysis of H2S-producing enzyme expression (CBS, CSE, 3MPST) via Western blot and RT-PCR.
• Assessment of H2S production in mesenteric artery homogenates.
• Evaluation of AP39-induced vasorelaxation with and without endothelium, and in the presence of enzyme inhibitors and channel blockers.

Main Results:

• CSE and 3MPST gene expression and all three enzyme protein expressions were confirmed in mesenteric arteries.
• AP39 and its moiety ADT-OH induced significant vasorelaxation, dependent on the endothelium, NO-cGMP signaling, and SKCa channels.
• Endogenous H2S contributes to AP39's mechanism, while KATP channels are not involved.

Conclusions:

• Mitochondria-targeted H2S donors, exemplified by AP39, exert direct vascular effects.
• AP39-induced vasodilation involves NO-cGMP and SKCa channels, with a role for endogenous H2S.
• These findings highlight the therapeutic potential of mitochondria-targeted H2S donors for cardiovascular diseases.