Inclisiran alleviates myocardial ischemia/reperfusion injury by blocking the HIF-1a/Myo1d-mediated M1 differentiation of macrophages
D Y Shi, Z Z Li, X P Dong, H Y Wang, X R Huang, L Guo, Z C Dong, Q Y Lin, B ZangAbstract
Background
Inflammatory cell infiltration represents a fundamental pathological mechanism that contributes to adverse ventricular remodeling and cardiac dysfunction in myocardial ischemia/reperfusion (I/R) injury. Proprotein convertase subtilisin/kexin type 9 (PCSK9) participates in processes including inflammation and apoptosis and is linked to a variety of cardiovascular diseases. Inclisiran, a small interfering RNA drug specifically targeting PCSK9, is currently employed for lipid-lowering therapy. Nevertheless, its function in myocardial I/R injury still awaits clarification.
Objective
This study aims to explore the role of Inclisiran in myocardial I/R injury and cardiac remodeling, and to clarify the molecular mechanism by which Inclisiran alleviates myocardial ischemia/reperfusion injury through regulating the M1 differentiation of macrophages, thereby providing new measures for the clinical prevention and treatment of myocardial I/R injury.
Methods
A myocardial ischemia/reperfusion model was established by ligating the left anterior descending coronary artery of mice. Echocardiography, laser speckle contrast imaging and TTC/Evans Blue staining were used to evaluate the cardiac function of mice. The degree of myocardial inflammation and apoptosis was assessed by histopathological staining, quantitative polymerase chain reaction and western blot. ChIP-seq, ChIP-qPCR and dual-luciferase reporter assay were used to verify the interaction between HIF-1α and Myo1d.
Results
Inclisiran attenuates I/R-induced cardiac dysfunction, reduced blood perfusion, increased infarct size, and myocardial cell inflammation and apoptosis. Mechanistically, Inclisiran reduces the M1 differentiation of macrophages by down-regulating the expression of HIF-1α and Myo1d, thereby alleviating myocardial I/R injury.
Conclusion
Inclisiran alleviates myocardial ischemia/reperfusion injury through blocking HIF-1α/Myo1d-mediated M1 differentiation of macrophages. To provide experimental evidence for the diagnosis of clinical myocardial I/R injury and the screening of new therapeutic targets.