Abstract
The cardiac microvascular reperfusion injury is characterized by the microvascular endothelial cells (CMECs) oxidative damage which is responsible for the progression of cardiac dysfunction. However, few strategies are available to reverse such pathologies. This study aimed to explore the mechanism by which oxidative stress induced CMECs death and the beneficial actions of melatonin on CMECs survival, with a special focused on IP3R-[Ca2+]c/VDAC-[Ca2+]m damage axis and the MAPK/ERK survival signaling. We found that oxidative stress induced by H2O2 significantly activated cAMP response element binding protein (CREB) that enhanced IP3R and VDAC transcription and expression, leading to [Ca2+]c and [Ca2+]m overload. High concentration of [Ca2+]m suppressed ΔΨm, opened mPTP, and released cyt-c into cytoplasm where it activated mitochondria-dependent death pathway. However, melatonin could protect CMECs against oxidative stress injury via stimulation of MAPK/ERK that inactivated CREB and therefore blocked IP3R/VDAC upregulation and [Ca2+]c/[Ca2+]m overload, sustaining mitochondrial structural and function integrity and ultimately blockading mitochondrial-mediated cellular death. In summary, these findings confirmed the mechanisms by which oxidative injury induced CMECs mitochondrial-involved death and provided an attractive and effective way to enhance CMECs survival.
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Acknowledgments
This study was supported by grants from the National 863 high technology R&D Program (No. 2011AA020101), National Natural Science Foundation of China (No: 81270186, 81102079), and Key Project of Natural Science Foundation of China (No: 81030002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Zhu, H., Jin, Q., Li, Y. et al. Melatonin protected cardiac microvascular endothelial cells against oxidative stress injury via suppression of IP3R-[Ca2+]c/VDAC-[Ca2+]m axis by activation of MAPK/ERK signaling pathway. Cell Stress and Chaperones 23, 101–113 (2018). https://doi.org/10.1007/s12192-017-0827-4
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DOI: https://doi.org/10.1007/s12192-017-0827-4