Myeloid-Specific Deletion of Lipid Plpp3 (Phosphate Phosphatase 3) Increases Cardiac Inflammation After Myocardial Infarction.
Myeloid-Specific Deletion of Lipid Plpp3 (Phosphate Phosphatase 3) Increases Cardiac Inflammation After Myocardial Infarction.
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脂质 Plpp3（磷酸酯磷酸酶 3）的髓系特异性缺失会增加心肌梗死后的心脏炎症。
DOI：
10.1161/atvbaha.122.317830
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Abdel-Latif,Ahmed
中科院分区：
文献类型：
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作者：
Tripathi,Himi;Shindo,Kazuhiro;Donahue,RenéeR;Gao,Erhe;Kuppa,Annapurna;ElKammar,Mahmoud;Morris,AndrewJ;Smyth,SusanS;Abdel-Latif,Ahmed
急性心肌梗死（MI）可导致全身炎症反应的激活，这对组织愈合至关重要，但不受控制的/长期的炎症对心脏功能恢复是有害的。1溶血磷脂酸调节单核细胞增多，并促进炎症的设置MI，因为我们最近报道。2溶血磷脂酸可被脂磷酸酶（LPPs）失活，其中LPP 3在血管损伤和组织愈合中起保护作用。3，4然而，髓样LPPs在MI后心脏炎症中的作用知之甚少。我们产生了具有骨髓特异性Plpp 3（编码LPP 3的基因）缺失（LysM-Plpp 3缺失）的小鼠模型。4该模型中的髓样细胞即使在体外刺激时也缺乏LPP 3的表达。4基线时心脏功能或炎症无显著差异（BSL，未手术的6周龄小鼠;图[A]至[C]）。LysM-Plpp 3 fl/fl和LysM-Plpp 3 fl/fl经历MI（永久性左前降支动脉结扎）或假手术。与LysM-Plpp 3fl/fl同窝对照相比，LPP 3的髓样缺失与较高的心脏Ly 6Chi单核细胞（CD 45 +/Ly 6 G/C+/CD 115 +; P< 0.01）和促炎性巨噬细胞（CD 45 +/F4 - 80 +/CD 86+细胞; P< 0.001和CD 45 +/F4-80+/CD 11b+细胞; P< 0.001）的平均数量相关（图[A]）。单核细胞增多症和骨髓造血髓系祖细胞增殖增加与严重的动脉粥样硬化和其他炎性疾病密切相关。MI前后分离的BM细胞的流式细胞术分析显示，LysM-Plpp 3μ M中造血干细胞/祖细胞、粒细胞-髓样祖细胞和普通髓样祖细胞的平均数量显著较高，这与心肌中浸润髓样细胞的平均数量较高相对应（图[B]）。总之，这些结果表明，髓样特异性LPP 3缺失导致髓样祖细胞增殖增加和MI后炎症反应加重。我们在基线、MI后48小时和30天进行了超声心动图检查。虽然两个实验组在基线时显示出相似的心脏功能，并且在48小时时显示出相当的下降，但我们在损伤后30天观察到LysM-Plpp 3β组的射血分数显著较低。类似地，我们观察到LysM-Plpp 3β小鼠在长期随访时心脏重塑更差，如收缩末期和舒张末期左心室直径更高所证明的（图[C]）。我们发现LysM-Plpp 3小鼠中毛细血管密度显著降低（通过Isolectin和CD 31染色评估），表明炎症反应加剧与血管生成减少之间存在联系（图[D]）。从机制上讲，LPP 3缺失与体外骨髓源性巨噬细胞的促血管生成分泌组减少相关（图[E]）。此外，LysM-Plpp 3小鼠的骨髓源性巨噬细胞对脂多糖刺激表现出加剧的炎症反应（图[F]）。𝚫随后，我们评估了梗塞大小、纤维化瘢痕扩张和胶原沉积，并在MI后30天观察到与LysM-Plpp 3fl/fl同窝对照相比，LysM-Plpp 3fl/fl小鼠中的瘢痕大小和纤维化面积显著更大（图[G]）。𝚫
Acute myocardial infarction (MI) leads to the activa-tion of a systemic inflammatory response, which is imperative for tissue healing, but uncontrolled/prolonged inflammation is detrimental to cardiac functional recovery. 1 Lysophosphatidic acid regulates monocytosis and promotes inflammation in the setting of MI as we have recently reported. 2 Lysophosphatidic acid can be inactivated by LPPs (lipid phosphate phosphatases) and one of these enzymes, LPP3 plays a protective role in vascular injury and tissue healing. 3, 4 However, the role of myeloid LPPs in cardiac inflammation post-MI is poorly understood. We generated a mouse model with myeloidspecific Plpp3 (gene encoding for LPP3) deletion (LysM-Plpp3𝚫). 4 Myeloid cells in this model lack the expression of LPP3 even when stimulated in vitro. 4 There were no significant differences in cardiac function or inflammation at baseline (BSL, unoperated 6-weekold mice; Figure [A] through [C]). LysM-Plpp3fl/fl and LysM-Plpp3𝚫 underwent MI (permanent left anterior descending artery ligation) or sham surgery. Myeloid deletion of LPP3 was associated with a higher mean number of cardiac Ly6Chi monocytes (CD45+/Ly6G/C+/CD115+; P< 0.01) and pro-inflammatory macrophages (CD45+/F4-80+/CD86+ cells; P< 0.001 and CD45+/F4-80+/CD11b+ cells; P< 0.001) compared with LysM-Plpp3fl/fl littermate controls (Figure [A]). Increased monocytosis and bone marrow hematopoietic myeloid progenitor cell proliferation have been closely linked to intense atherogenesis5 and other inflammatory conditions. Flow cytometry analyses of BM cells isolated before and after MI revealed a significantly higher mean number of hematopoietic stem/progenitor cells, granulocyte-myeloid progenitors, and common myeloid progenitors in LysM-Plpp3𝚫, corresponding with the higher mean number of infiltrating myeloid cells in the myocardium (Figure [B]). Together, these results demonstrate that myeloid-specific LPP3 deletion results in increased myeloid progenitor cell proliferation and an aggravated inflammatory response after MI. We performed echocardiography at baseline, 48 hours, and 30 days post-MI. While both experimental groups showed similar cardiac function at baseline and comparable drop at 48 hours, we observed a significantly lower ejection fraction in LysM-Plpp3𝚫 group at 30 days after injury. Similarly, we observed worse cardiac remodeling, as evidenced by the higher end-systolic and enddiastolic left ventricular diameters, at long-term follow-up in LysM-Plpp3𝚫 mice (Figure [C]). We found a significant decrease in capillary density (as assessed by Isolectin and CD31 staining) in LysM-Plpp3𝚫 mice suggesting a link between the exacerbated inflammatory response and reduced angiogenesis (Figure [D]). Mechanistically, LPP3 deletion was associated with a reduction in proangiogenic secretome from bone marrow–derived macrophages in vitro (Figure [E]). Furthermore, bone marrow–derived macrophages from LysM-Plpp3𝚫 mice showed exacerbated inflammatory response to lipopolysaccharide stimulation (Figure [F]). Subsequently, we assessed the infarct size, fibrotic scar expansion, and collagen deposition and observed a significantly larger scar size and fibrotic area in LysM-Plpp3𝚫 mice compared with LysM-Plpp3fl/fl littermate controls at 30 days after MI (Figure [G]).