Abstract

A groundbreaking study conducted by prominent researchers at Zhongshan Hospital, Fudan University, and its affiliating Shanghai Institute of Cardiovascular Diseases, reveals the potential of nicorandil, an ATP-sensitive K+ channel opener, to counteract cardiac microvascular ferroptosis — a detrimental process involved in diabetic cardiomyopathy. Through modulation of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway, nicorandil emerges as a promising therapeutic agent. This research paves the way for novel interventions in managing vascular complications associated with diabetes.

Introduction

Diabetic cardiomyopathy stands as a formidable challenge in the medical community, characterized by impaired cardiac function and microvascular dysfunction, ultimately leading to heart failure. The intricacies of diabetic cardiomyopathy are manifold, but recent evidence points to ferroptosis, a specialized form of cell death driven by iron-dependent lipid peroxidation, as a key contributor to the pathology of this condition. In light of this, the therapeutic potential of targeting ferroptosis warrants extensive exploration.

Body

Researchers at Zhongshan Hospital have embarked on a mission to dissect the role of ferroptosis in diabetic cardiomyopathy and to assess the therapeutic benefits of nicorandil — a medication traditionally used to treat angina pectoris — in this context. Their findings, detailed in the January 2024 issue of “Pharmacological Research,” offer new insights into the cellular mechanisms driving diabetic heart disease and suggest a potential new avenue for treatment.

In this study, the team, led by Dr. Chen Zhangwei and supported by colleagues including Dr. Li Su, Dr. Liu Muyin, and Dr. Yin Ming, amongst others, employed several sophisticated techniques including lectin perfusion assays, mt-Keima transfection, and transmission electron microscopy to carefully analyze the impact of ferroptosis on cardiac microvascular endothelial cells. The meticulous approach adopted led to the detection and analysis of ferroptosis at a molecular level using mRNA sequencing, fluorescence staining, and western blotting. Immunofluorescence staining was pivotal in elucidating the mitochondrial localization of critical proteins involved in the process.

Of cardinal importance in their discoveries was the relationship between nicorandil and the AMPK-Parkin-ACSL4 signaling pathway within the mitochondria. The key findings were particularly enlightening, indicating nicorandil’s ability to improve cardiac function and microvascular integrity by mitigating ferroptosis associated with long-standing diabetes. Specifically, the drug was found to promote mitophagy — the process by which cells remove defective mitochondria — in a manner dependent on the Pink1/Parkin pathway.

The study found that in a diabetic milieu, ferroptosis is not only present but also that the Pink1/Parkin-dependent mitophagy is suppressed, adding to the burden of microvascular endothelial damage. However, upon treating with nicorandil, there was a notable upsurge in the phosphorylation level of AMPKα1 and its consequent translocation to the mitochondria. This occurrence appeared to obstruct the mitochondrial translocation of ACSL4, a lipid metabolism-associated protein found to facilitate ferroptosis via mitophagy suppression and thus protected against mitochondria-associated ferroptosis.

Intriguingly, the benefits of nicorandil were paralleled when mitochondria-localized AMPKα1 was overexpressed independently, reinforcing the conclusion that nicorandil’s protective effects against ferroptosis are mediated by this particular signaling pathway. Therefore, the study posits that nicorandil serves a dual function in diabetic cardiomyopathy — as an anti-anginal therapy, and as a protector against ferroptosis by modulating mitochondrial function.

Conclusion

The compelling data brought forth by Dr. Chen Zhangwei and his team from Zhongshan Hospital, confirmed by a robust and thorough investigation, demonstrate how the mitigation of mitochondria-associated ferroptosis via the AMPK-Parkin-ACSL4 signaling pathway by nicorandil holds immense promise for the treatment of diabetic cardiomyopathy. Not only does this signal a significant advance in understanding this complex disease, it also opens doors to a multi-faceted drug approach, warranting further clinical investigation.

Recommendation for Further Research

To fully understand the implications of this study and the potential for widespread clinical application, it is essential that further research be conducted. This would involve the testing of nicorandil’s effects in a broader diabetic population and assessing long-term outcomes relative to cardiac health and microvascular integrity.

Copyright Information
Copyright © 2024 The Authors. Published by Elsevier Ltd. All rights reserved. (DOI: 10.1016/j.phrs.2024.107057)

References

1. Zhangwei, C., Su, L., Muyin, L., Ming, Y., Jinxiang, C., Youran, L., … Chenguang, L. (2024). Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway. Pharmacological Research, 200, 107057. https://doi.org/10.1016/j.phrs.2024.107057
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Keywords

1. Diabetic cardiomyopathy treatment
2. Cardiac microvascular ferroptosis
3. Nicorandil ferroptosis protection
4. AMPK-Parkin-ACSL4 pathway
5. Mitochondrial dysfunction in diabetes