Abstract
Genetically human apolipoprotein E (APOE) ε32 is associated with a decreased risk of ischemic heart disease. ApoE deficiency in mice impairs infarct healing after myocardial infarction (MI). After the ischemic injury, a large number of neutrophils are firstly recruited into the infarct zone and then degrade dead material and promote reparative phase transformation. The role of ApoE in inflammation response in the early stage of MI remains largely unclear. In this study, we investigated the effect of ApoE deficiency on neutrophils' function and myocardial injury after myocardial infarction. By left coronary artery ligation in ApoE −/− and wild-type (WT) mice, we observed increased infarct size and neutrophil infiltration in ApoE −/− mice. Within the infarct zone, more neutrophil extracellular traps (NETs) were observed in ApoE −/− mice, while increased ex vivo NET formation was detected in ApoE −/− mouse-derived neutrophils through the NADPH oxidase-ROS-dependent pathway. Suppressing overproduced NETs reduced myocardial injury in ApoE −/− mice after ligation. In general, our findings reveal a critical role of apolipoprotein E in regulating Ly6G+ neutrophil activation and NET formation, resulting in limiting myocardial injury after myocardial infarction. In such a process, apolipoprotein E regulates NET formation via the ROS-MAPK-MSK1 pathway.
Highlights
Nowadays, the mortality due to cardiovascular disease still ranks as the top among all noncommunicable diseases globally, and the prevalence of ischemic heart disease keeps rising rapidly over the past two decades in China [1, 2]
Myocardial Injury Is Aggravated in ApoE-/- Mice after Ligation
The result of tetrazolium chloride (TTC) staining showed that the infarct size was significantly larger in ApoE-/- mice compared to WT counterparts (Figures 1(a) and 1(b))
Summary
The mortality due to cardiovascular disease still ranks as the top among all noncommunicable diseases globally, and the prevalence of ischemic heart disease keeps rising rapidly over the past two decades in China [1, 2]. The formation of atherosclerosis, the most common cause of ischemic heart disease, is due to low-density lipoprotein accumulation in the subendothelial space [3]. Apolipoprotein E deficiency (ApoE-/-) mice are wildly used in order to mimic and better understand this hypercholesterolemiaassociated process. Human APOE has three major allelic variants (ε2, ε3, and ε4), and most people carry at least one ε3. The ε32 genotype is associated with a decreased risk of ischemic heart disease [4]. Current researches view ApoE-/- more as a tool to reach hypercholesterolemia conditions in vivo in order to Oxidative Medicine and Cellular Longevity better understand atherosclerosis or the myocardial ischemia process. The role of ApoE itself has not been fully investigated
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