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Isorhapontigenin attenuates cardiac microvascular injury in diabetes mellitus via the inhibition of mitochondrial-derived ferroptosis through PRDX2-MFN2-ACSL4 pathways.

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posted on 2022-11-11, 18:11 authored by Yuqiong Chen, Su Li, Ming Yin, Yafei Li, Chao Chen, Jun Zhang, Kangyun Sun, Xiangqing Kong, Zhangwei Chen, Juying Qian

Ferroptosis is a newly identified form of regulated cell death that is driven by iron overload and uncontrolled lipid peroxidation, but the role of ferroptosis in cardiac microvascular dysfunction remains unclear. Isorhapontigenin (ISO) is an analog of resveratrol and possesses strong antioxidant capacity and cardiovascular protective effects. Moreover, ISO has been shown to alleviate iron-induced oxidative damage and lipid peroxidation in mitochondria. Therefore, the present study aimed to explore the benefits of ISO treatment on cardiac microvascular dysfunction in diabetes mellitus and the possible mechanisms involved, with a focus on ferroptosis and mitochondria. Our data revealed that ISO treatment improved microvascular density and perfusion in db/db mice by mitigating vascular structural damage, normalizing nitric oxide (NO) production via eNOS activation, and enhancing angiogenetic ability via VEGFR2 phosphorylation. PRDX2 was identified as a downstream target of ISO, and endothelial-specific overexpression of PRDX2 exerted effects on the cardiac microvascular function that were similar to those of ISO treatment. In addition, PRDX2 mediated the inhibitive effects of ISO treatment on ferroptosis by suppressing oxidative stress, iron overload and lipid peroxidation. Further study suggested that mitochondrial dynamics and dysfunction contributed to ferroptosis, and ISO treatment or PRDX2 overexpression attenuated mitochondrial dysfunction via MFN2-dependent mitochondrial dynamics. Moreover, MFN2 overexpression suppressed the mitochondrial translocation of ACSL4, ultimately inhibiting mitochondrial-derived ferroptosis. In contrast, enhancing mitochondrial-derived ferroptosis via ACSL4 abolished the protective effects of ISO treatment on cardiac microcirculation. Taken together, the results of the present work demonstrated the beneficial effects of ISO treatment on cardiac microvascular protection in diabetes mellitus by suppressing mitochondrial-derived ferroptosis through PRDX2-MFN2-ACSL4 pathways.

Funding

This study was supported by National Natural Science Foundation of China (Grant Nos. 82200449, 82170338, 81970295) and Gusu School of Nanjing Medical University (Grant Nos. GSBSHKY202118).

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