Abstract 13420: Nicorandil Suppresses Mitochondria-Associated Ferroptosis to Attenuates Cardiac Microvascular Disorder in Diabetes: Role of Mitochondria-Localized AMPKα1

Backgrounds: Common metabolic risk factors, including diabetes, promote cardiac microvascular disorder (CMD), which contributes to ischemia with no obstructive coronary artery disease (INOCA). Recently, our group demonstrated the inhibition of mitochondria-associated ferroptosis in CMD alleviates diabetic cardiomyopathy. Nicorandil (Nic) is recommended as an anti-angina drug for INOCA, whether Nic could inhibit ferroptosis in CMD is not discussed.

Aims: To explore the benefits of Nic on diabetes-induced CMD and ferroptosis.

Methods: Nic was orally administered to db/db mice for 6 months. Mitochondria-localized AMPKα1 (mitoAMPKα1) was overexpressed in endothelial cells. Ferroptosis and related signaling pathways were assessed by mRNA sequencing assays, fluorescence staining and western blot.

Results: Nic significantly alleviated CMD and diabetic cardiomyopathy as evidenced by improved cardiac microvascular perfusion and anatomical structure. mRNA sequencing assays revealed significant enriched pathways related to ferroptosis, mitophagy and AMPK signaling pathway after Nic treatment. Moreover, Nic reversed genes expression involved in ferroptosis and reduced mitochondrial and cellular lipid peroxidation (LPO) formation. Nic increased AMPKα1 phosphorylation and promoted its translocation to mitochondria, in where the phosphorylated AMPKα1 stimulated Parkin-dependent mitophagy and reduced mitochondrial translocation of ACSL4 to inhibit ferroptosis. Endothelium-specific overexpression of an active form of mitoAMPKα1 showed similar benefits as Nic to inhibit cardiac microvascular ferroptosis and improved myocardial dysfunction and pathological remodeling.

Conclusions: The present work identified mitoAMPKα1 as the potential target for Nic to alleviate mitochondria-associated ferroptosis in diabetes-induced CMD.