Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density
Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density
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DOI：
10.1152/ajpheart.00755.2010
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发表时间：
2011-11-01
影响因子：
4.8
通讯作者：
Chan, Tung O.
中科院分区：
文献类型：
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作者：
Li, Xue;Mikhalkova, Deana;Chan, Tung O.
Li X，Mikhalkova D，Gao E，Zhang J，Myers V，Zincarelli C，Lei Y，Song J，Koch WJ，Peppel K，Cheung JY，Feldman AM，Chan TO. Akt 2缺陷小鼠缺血再灌注后心肌损伤与心脏巨噬细胞密度增加相关Am J Physiol Heart Circ Physiol 301：H1932-H1940，2011.首次发表于2011年9月2日; doi：10.1152/ajpheart.00755.2010.- Akt 2蛋白激酶已被证明可以促进包括巨噬细胞在内的几种细胞类型中的细胞迁移和肌动蛋白聚合。由于迁移性巨噬细胞构成心肌缺血后的重要炎症反应，我们确定了缺乏Akt 2（Akt 2-KO）的小鼠在缺血再灌注（I/R）损伤和冷冻损伤后的心脏巨噬细胞表达。在I/R后7天，与野生型（WT）小鼠相比，Akt 2-KO心脏组织显示巨噬细胞标志物（半乳糖凝集素3和F4/80）的免疫组织化学染色增加，表明损伤的Akt 2-KO心肌中巨噬细胞密度增加。这种变化是时间依赖性的，因为在I/R后3天WT和Akt 2-KO心肌之间的巨噬细胞密度相似，但到I/R后7天和14天，Akt 2-KO心肌中的巨噬细胞密度显著增加。同时，在接受I/R的Akt 2-KO小鼠中，梗死面积更大，心脏功能降低。然而，当冷冻梗死在WT和Akt 2-KO小鼠的前壁产生相似的梗死面积时，Akt 2-KO小鼠心肌中的巨噬细胞密度仍然较高，这表明Akt 2调节心肌巨噬细胞密度，与梗死面积无关。一致地，来自Akt 2-KO小鼠的骨髓在C57/B6 WT和Akt 2-KO受体小鼠中均增强心肌巨噬细胞密度。最后，巨噬细胞和心肌细胞的相互离体共培养显示，与WT同窝对照相比，活化的Akt 2-KO腹膜巨噬细胞的移动性和粘附性降低。因此，尽管Akt-2 KO小鼠不影响损伤后的初始炎症反应，并且Akt 2缺陷已显示损害巨噬细胞中的细胞迁移或运动性，但我们的数据提示了一种新的机制，其中Akt 2-KO巨噬细胞的保留增加导致心肌空间中心脏Akt 2-KO巨噬细胞密度增加。
Li X, Mikhalkova D, Gao E, Zhang J, Myers V, Zincarelli C, Lei Y, Song J, Koch WJ, Peppel K, Cheung JY, Feldman AM, Chan TO. Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density. Am J Physiol Heart Circ Physiol 301: H1932-H1940, 2011. First published September 2, 2011; doi:10.1152/ajpheart.00755.2010.-Akt2 protein kinase has been shown to promote cell migration and actin polymerization in several cell types, including macrophages. Because migrating macrophages constitute an important inflammatory response after myocardial ischemia, we determined cardiac macrophage expression after ischemia-reperfusion (I/R) injury and cryo-injury in mice lacking Akt2 (Akt2-KO). At 7 days post-I/R, Akt2-KO cardiac tissues showed an increase in immunohistochemical staining for macrophage markers (Galectin 3 and F4/80) compared with wild-type (WT) mice, indicating macrophage density was increased in the injured Akt2-KO myocardium. This change was time dependent because macrophage density was similar between WT and Akt2-KO myocardium at 3 days post-I/R, but by 7 and 14 days post-I/R, macrophage density was significantly increased in Akt2-KO myocardium. Concomitantly, infarct size was larger and cardiac function was reduced in Akt2-KO mice subjected to I/R. However, when cryo-infarction produced similar infarct sizes in the anterior wall in both WT and Akt2-KO mice, macrophage density remained higher in Akt2-KO mouse myocardium, suggesting Akt2 regulates myocardial macrophage density independent of infarct size. Consistently, bone marrow from Akt2-KO mice enhanced myocardial macrophage density in both C57/B6 WT and Akt2-KO recipient mice. Finally, reciprocal ex-vivo coculturing of macrophages and cardiac myocytes showed that activated Akt2-KO peritoneal macrophages had reduced mobility and adhesion when compared with WT littermate controls. Thus, although Akt-2 KO mice did not affect the initial inflammation response after injury and Akt2 deficiency has been shown to impair cell migration or motility in macrophages, our data suggested a novel mechanism in which increasing retention of Akt2-KO macrophages resulted in increasing cardiac Akt2-KO macrophage density in the myocardial space.