Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density

Abstract

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.heart; protein kinase B; cryo-infarction; inflammation; peritoneal macrophages AKT SERINE-THREONINE kinase, also known as protein kinase B, is composed of a family of three highly homologous members: Akt1, Akt2, and Akt3. The three Akt isotypes share over 85% homology with similar catalytic characteristics and can block cell apoptosis and enhance cell growth and metabolism (37). Interestingly, Akt1 and Akt2 functions diverge at cell migration. Activated Akt1 inhibits cell migration by inhibiting nuclear factor of activated T-cells, ERK, and tuberous sclerosis protein 2 signals (5). On the other hand, activated Akt2 promotes cell migration through ␤ 1 integrin in breast cancer cells (21) or through phosphorylation of girdin or cofilin in glioma cells and macrophages (39,40). In the heart, viralmediated gene transfer of activated Akt1 protein kinase into rodent myocardium protected against is...

TRPM2 Channels Protect against Cardiac Ischemia-Reperfusion Injury

“…Taking derivatives, ⌬I/⌬E m ϭ G. G Ca /G Na is given by the ratio of the slopes of I versus E m plots with Ca 2ϩ or Na ϩ as the permeant ion. I/R Surgery in Mice-I/R surgery was performed as previously described (23,24). Briefly, male WT and KO mice (8 -10 weeks) were anesthetized with 2% isoflurane, and the heart was exposed through a left thoracotomy at the fifth intercostal space.…”

Ticagrelor attenuates myocardial ischaemia–reperfusion injury possibly through downregulating galectin‐3 expression in the infarct area of rats

“…Li et al . 22 found that enhanced myocardial injury after I/R injury in mice deficient in Akt2 was associated with increased cardiac macrophage density and macrophage marker galectin‐3. Sanchez‐Mas et al .…”

Cardioprotection by PI3K-mediated signaling is required for anti-arrhythmia and myocardial repair in response to ischemic preconditioning in infarcted pig hearts

“…Although it is clear that LY294002 exerted significant effects on many of the above-mentioned situations, the effects of LY294002 on the survival function (Figure 1), malignant arrhythmia initial episode time (Figure 2), and LVEF, LVFS, LVEDIVST, and LVEDPWT ( Figure 3) were similar between the LYIPLI group and the LYLI group, corresponding with the similar change of pSer473 between the LYIPLI group and the LYLI group (Figure 6), and this could mean that Akt has other effects independent of IP and myocardial infarction, such as autophagy, 24 neuroprotective potential, 25 and decreasing macrophage retention. 26 Although LY294002 has been extremely useful and is still widely employed as a research probe, it has a very significant limitation: LY294002 is a weak inhibitor with only micromolar potency. 23 Our study showed similar findings: in comparison with the LYLI group, fewer arrhythmia episodes and cumulative episode time (Figure 2b), smaller LVEDV, LVESV, LVEDD, and LVESD (Figure 3), lower inflammation (Figure 4), less infarct size (Figures 5a and c), and collagen content (Figures 5b and e), and greater viable myocardium (Figure 5d) were seen in the LYIPLI group, in accordance with higher expression of Akt, Cx43 (Figure 6), Ang-1, bFGF, and VEGF, more blood vascular density, and collateral circulation ( Figure 7).…”