Inclisiran attenuates myocardial ischemia/reperfusion injury by inhibiting macrophage M1 polarization
- 1Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011 China
- 2Department of Geriatrics, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011 China
- 3Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011 China
Abstract
Macrophage polarization is pivotal in myocardial ischemia/reperfusion (I/R) injury. Inclisiran is a small interfering RNA agent that lowers low-density lipoprotein cholesterol by targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). However, whether Inclisiran exerts LDL-C-independent cardioprotective effects within the acute I/R window remains unclear. In this study, wild-type C57BL/6J mice were pretreated with Inclisiran before I/R surgery. Myocardial injury was assessed by echocardiography, laser speckle contrast imaging, and TTC/Evans Blue staining. Macrophage polarization and its direct impact on cardiomyocytes or fibroblasts were investigated in co-culture system in vitro. Target gene screening was performed by chromatin immunoprecipitation (ChIP)-sequencing, and transcriptional regulation was validated by dual-luciferase assay and ChIP-qPCR. Protein interaction was confirmed by molecular docking, surface plasmon resonance, and co-immunoprecipitation. Our results demonstrated that Inclisiran significantly attenuated myocardial injury and dysfunction, inhibited macrophage M1 polarization, reduced cardiomyocyte apoptosis, and suppressed fibroblast activation. Mechanistically, Inclisiran disrupted the direct interaction between PCSK9 and JNK, thereby blocking the HIF-1α-mediated transcriptional regulation of Myo1d, and ultimately suppressing macrophage M1 polarization. In conclusion, Inclisiran alleviates myocardial I/R injury by targeting the JNK–HIF-1α–Myo1d signaling axis. These findings identify a previously unrecognized cardioprotective mechanism that is LDL-C-independent within the acute I/R window, suggesting Inclisiran as a promising therapeutic strategy for ischemic cardiomyopathy.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10495-026-02475-z.
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BibTeX
@article{shi2026inclisiran,
title = {{Inclisiran attenuates myocardial ischemia/reperfusion injury by inhibiting macrophage M1 polarization}},
author = {Ding-Yu Shi and Zi-Zhuo Li and Jun-Qin Bai and Xiao-Peng Dong and Wei Zhang and Hui-Yang Wang and Xiao-Rong Huang and Zhi-Chao Dong and Lei Guo and Qiu-Yue Lin and Bo Zhang},
journal = {Apoptosis},
year = {2026},
month = nov,
doi = {10.1007/s10495-026-02475-z},
url = {https://doi.org/10.1007/s10495-026-02475-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Inclisiran attenuates myocardial ischemia/reperfusion injury by inhibiting macrophage M1 polarization
AU - Ding-Yu Shi
AU - Zi-Zhuo Li
AU - Jun-Qin Bai
AU - Xiao-Peng Dong
AU - Wei Zhang
AU - Hui-Yang Wang
AU - Xiao-Rong Huang
AU - Zhi-Chao Dong
AU - Lei Guo
AU - Qiu-Yue Lin
AU - Bo Zhang
PY - 2026
DA - 2026/11/03
JO - Apoptosis
DO - 10.1007/s10495-026-02475-z
UR - https://doi.org/10.1007/s10495-026-02475-z
AB - Macrophage polarization is pivotal in myocardial ischemia/reperfusion (I/R) injury. Inclisiran is a small interfering RNA agent that lowers low-density lipoprotein cholesterol by targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). However, whether Inclisiran exerts LDL-C-independent cardioprotective effects within the acute I/R window remains unclear. In this study, wild-type C57BL/6J mice were pretreated with Inclisiran before I/R surgery. Myocardial injury was assessed by echocardiography, laser speckle contrast imaging, and TTC/Evans Blue staining. Macrophage polarization and its direct impact on cardiomyocytes or fibroblasts were investigated in co-culture system in vitro. Target gene screening was performed by chromatin immunoprecipitation (ChIP)-sequencing, and transcriptional regulation was validated by dual-luciferase assay and ChIP-qPCR. Protein interaction was confirmed by molecular docking, surface plasmon resonance, and co-immunoprecipitation. Our results demonstrated that Inclisiran significantly attenuated myocardial injury and dysfunction, inhibited macrophage M1 polarization, reduced cardiomyocyte apoptosis, and suppressed fibroblast activation. Mechanistically, Inclisiran disrupted the direct interaction between PCSK9 and JNK, thereby blocking the HIF-1α-mediated transcriptional regulation of Myo1d, and ultimately suppressing macrophage M1 polarization. In conclusion, Inclisiran alleviates myocardial I/R injury by targeting the JNK–HIF-1α–Myo1d signaling axis. These findings identify a previously unrecognized cardioprotective mechanism that is LDL-C-independent within the acute I/R window, suggesting Inclisiran as a promising therapeutic strategy for ischemic cardiomyopathy. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10495-026-02475-z.
SN - 1360-8185
SN - 1573-675X
ER -