VDAC1-NF-κB/p65-mediated S100A16 contributes to myocardial ischemia/reperfusion injury by regulating oxidative stress and inflammatory response via calmodulin/CaMKK2/AMPK pathway

Congna Zi; Xian Ma; Maodong Zheng; Ying Zhu

doi:10.1016/j.ejphar.2024.177158

VDAC1-NF-κB/p65-mediated S100A16 contributes to myocardial ischemia/reperfusion injury by regulating oxidative stress and inflammatory response via calmodulin/CaMKK2/AMPK pathway

Eur J Pharmacol. 2024 Nov 28:987:177158. doi: 10.1016/j.ejphar.2024.177158. Online ahead of print.

Authors

Congna Zi¹, Xian Ma², Maodong Zheng³, Ying Zhu⁴

Affiliations

¹ Department of Anesthesiology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China. Electronic address: Jn18mn16gmh@126.com.
² Department of Blood Transfusion, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China. Electronic address: maxian@hbbfyfy.com.
³ Department of Pharmacy, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China.
⁴ Department of Anesthesiology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China.

PMID: 39613175
DOI: 10.1016/j.ejphar.2024.177158

Abstract

Myocardial injury triggers intense inflammatory reactions and oxidative stress responses. S100 calcium-binding protein A16 (S100A16), a multi-functional calcium (Ca²⁺)-binding protein, participates in inflammatory responses and contributes to ischemia/reperfusion (I/R) injury. Nevertheless, the precise mechanism by which S100A16 operates in myocardial I/R injury remains uncertain. Cardiac I/R injury was produced by ligation/release of the left anterior descending artery, and mouse cardiac cells were subjected to hypoxia/reoxygenation (H/R) to determine the biological effects in vitro. We demonstrated that S100A16 was upregulated in the ischemic hearts and cardiac cells after I/R and H/R injury. Adenovirus-mediated S100A16 inhibition led to a considerable improvement in cardiac function with a reduced infarct size, accompanied by a reduction in cardiomyocyte apoptosis. Similar effects of S100A16 inhibition on inflammation and reactive oxygen species (ROS) production were observed in cultured cardiomyocytes. Importantly, we showed that I/R and H/R treatment upregulated the expression of voltage-dependent anion channel 1 (VDAC1), which subsequently activated NF-κB/p65 to facilitate the binding of NF-κB/p65 to the S100A16 promoter, thereby activating the transcription and expression of S100A16. Mechanically, S100A16 responded to increasing Ca²⁺ and interacted with calmodulin (CaM) to regulate the activation of calcium/calmodulin-dependent protein kinase 2 (CAMKK2)/AMPK pathway. In conclusion, VDAC1 sustained the NF-κB p65 pathway activation to elicit increased S100A16 expression, contributing to myocardial damage and heart failure post-I/R via the CaM/CaMKK2/AMPK pathway. This study revealed a crucial role of the VDAC1-S100A16 axis in the process of myocardial I/R injury, providing novel molecular targets for the treatment of cardiac conditions associated with I/R injury.

Keywords: AMPK pathway; Myocardial ischemia/reperfusion injury; Oxidative stress; S100A16; VDAC1.