Ac-SDKP decreases mortality and cardiac rupture after acute myocardial infarction

The natural peptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) decreases inflammation in chronic diseases such as hypertension and heart failure. However, Ac-SDKP effects on acute inflammatory responses during myocardial infarction (MI) are unknown. During the first 72 hours post-MI, neutrophils, M1 macrophages (pro-inflammatory), and M2 macrophages (pro-resolution) and release of myeloperoxidase (MPO) and matrix metalloproteinases (MMP) are involved in cardiac rupture. We hypothesized that in the acute stage of MI, Ac-SDKP decreases the incidence of cardiac rupture and mortality by preventing immune cell infiltration as well as by decreasing MPO and MMP expression. MI was induced by ligating the left descending coronary artery in C57BL/6 mice. Vehicle or Ac-SDKP (1.6 mg/kg/d) was infused via osmotic minipump. Cardiac immune cell infiltration was assessed by flow cytometry, cardiac MPO and MMP levels were measured at 24–48 hrs post-MI. Cardiac rupture and mortality incidence were determined at 7 days post-MI. In infarcted mice, Ac-SDKP significantly decreased cardiac rupture incidence from 51.0% (26 of 51 animals) to 27.3% (12 of 44) and mortality from 56.9% (29 of 51) to 31.8% (14 of 44). Ac-SDKP reduced M1 macrophages in cardiac tissue after MI, without affecting M2 macrophages and neutrophils. Ac-SDKP decreased MMP-9 activation in infarcted hearts with no changes on MPO expression. Ac-SDKP prevents cardiac rupture and decreases mortality post-acute MI. These protective effects of Ac-SDKP are associated with decreased pro-inflammatory M1 macrophage infiltration and MMP-9 activation.天然肽N-乙酰基-丝氨酰-天冬氨酰-赖氨酰-脯氨酸（Ac-SDKP）可减轻高血压、心力衰竭等慢性疾病的炎症反应。然而，Ac-SDKP对心肌梗死（myocardial infarction, MI）急性期炎症应答的影响尚不明确。在心肌梗死后的最初72小时内，中性粒细胞、促炎型M1巨噬细胞、促消退型M2巨噬细胞的浸润，以及髓过氧化物酶（myeloperoxidase, MPO）与基质金属蛋白酶（matrix metalloproteinases, MMP）的释放，均与心脏破裂的发生密切相关。本研究推测，在心肌梗死急性期，Ac-SDKP可通过抑制免疫细胞浸润、降低MPO与MMP的表达，减少心脏破裂的发生率并降低死亡率。本研究通过结扎C57BL/6小鼠的左冠状动脉构建心肌梗死模型，通过渗透微泵向小鼠输注溶剂对照或Ac-SDKP（1.6 mg/kg/d）。于心肌梗死后24~48小时，通过流式细胞术评估心脏免疫细胞浸润情况，并检测MPO与MMP的水平；于心肌梗死后7天统计心脏破裂发生率与死亡率。实验结果显示，在造模小鼠中，Ac-SDKP可将心脏破裂发生率从51.0%（51只小鼠中26只）显著降至27.3%（44只小鼠中12只），并将死亡率从56.9%（51只小鼠中29只）降至31.8%（44只小鼠中14只）。Ac-SDKP可减少心肌梗死后心脏组织中的M1巨噬细胞浸润，而对M2巨噬细胞与中性粒细胞无显著影响；同时可降低梗死心脏中MMP-9的活化水平，但对MPO的表达无明显改变。综上，Ac-SDKP可预防急性心肌梗死后的心脏破裂并降低死亡率，其保护作用与减少促炎型M1巨噬细胞浸润以及抑制MMP-9活化密切相关。