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Inhibition of Janus activated kinase-3 protects against myocardial ischemia and reperfusion injury in mice.

Oh YB, Ahn M, Lee SM, Koh HW, Lee SH, Kim SH, Park BH - Exp. Mol. Med. (2013)

Bottom Line: Treatment with JANEX-1 significantly decreased plasma creatine kinase and lactate dehydrogenase activities, reduced infarct size, reversed I/R-induced functional deterioration of the myocardium and reduced myocardial apoptosis.Histological analysis revealed an increase in neutrophil and macrophage infiltration within the infarcted area, which was markedly reduced by JANEX-1 treatment.Of note, however, JANEX-1 did not affect the expression of IL-8 and MCP-1 in the myocardium.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.

ABSTRACT
Recent studies have documented that Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathway can modulate the apoptotic program in a myocardial ischemia/reperfusion (I/R) model. To date, however, limited studies have examined the role of JAK3 on myocardial I/R injury. Here, we investigated the potential effects of pharmacological JAK3 inhibition with JANEX-1 in a myocardial I/R model. Mice were subjected to 45 min of ischemia followed by varying periods of reperfusion. JANEX-1 was injected 1 h before ischemia by intraperitoneal injection. Treatment with JANEX-1 significantly decreased plasma creatine kinase and lactate dehydrogenase activities, reduced infarct size, reversed I/R-induced functional deterioration of the myocardium and reduced myocardial apoptosis. Histological analysis revealed an increase in neutrophil and macrophage infiltration within the infarcted area, which was markedly reduced by JANEX-1 treatment. In parallel, in in vitro studies where neutrophils and macrophages were treated with JANEX-1 or isolated from JAK3 knockout mice, there was an impairment in the migration potential toward interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively. Of note, however, JANEX-1 did not affect the expression of IL-8 and MCP-1 in the myocardium. The pharmacological inhibition of JAK3 might represent an effective approach to reduce inflammation-mediated apoptotic damage initiated by myocardial I/R injury.

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Effects of Janus-activated kinase 3 (JAK3) suppression on chemokine-directed cell migration. Neutrophils (a) and macrophages (b) that had been incubated with the indicated concentrations of JANEX-1 for 2 h were allowed to migrate through a polycarbonate filter for 2 h toward interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively. Neutrophils (c) and macrophages (d) isolated from wild-type (WT) or JAK3 knockout (KO) mice were allowed to migrate through a polycarbonate filter for 2 h toward IL-8 and MCP-1, respectively. The number of cells present in lower chamber was counted. Values are the mean±s.e.m. of three independent experiments (n=6 mice per group). *P<0.05, **P<0.01 vs vehicle; ##P<0.01 vs WT.
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fig5: Effects of Janus-activated kinase 3 (JAK3) suppression on chemokine-directed cell migration. Neutrophils (a) and macrophages (b) that had been incubated with the indicated concentrations of JANEX-1 for 2 h were allowed to migrate through a polycarbonate filter for 2 h toward interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively. Neutrophils (c) and macrophages (d) isolated from wild-type (WT) or JAK3 knockout (KO) mice were allowed to migrate through a polycarbonate filter for 2 h toward IL-8 and MCP-1, respectively. The number of cells present in lower chamber was counted. Values are the mean±s.e.m. of three independent experiments (n=6 mice per group). *P<0.05, **P<0.01 vs vehicle; ##P<0.01 vs WT.

Mentions: To define the molecular mechanisms underlying JANEX-1-mediated inhibition of neutrophil and macrophage infiltration within the infarcted hearts, we isolated neutrophils and macrophages from mice and performed migration assay. Treatment of neutrophils with JANEX-1 inhibited the migration of these cells toward IL-8 in a concentration-dependent manner (Figure 5a). Similarly, macrophage migration toward MCP-1 was also effectively inhibited by JANEX-1 (Figure 5b). Neutrophils and macrophages isolated from JAK3 KO mice also showed decreased migration potential as compared with those cells isolated from normal mice (Figures 5c and d). These results suggest that in vivo JANEX-1-mediated inhibition of neutrophil and macrophage infiltration within the infarcted hearts was due to impaired migration potential of these cells.


Inhibition of Janus activated kinase-3 protects against myocardial ischemia and reperfusion injury in mice.

Oh YB, Ahn M, Lee SM, Koh HW, Lee SH, Kim SH, Park BH - Exp. Mol. Med. (2013)

Effects of Janus-activated kinase 3 (JAK3) suppression on chemokine-directed cell migration. Neutrophils (a) and macrophages (b) that had been incubated with the indicated concentrations of JANEX-1 for 2 h were allowed to migrate through a polycarbonate filter for 2 h toward interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively. Neutrophils (c) and macrophages (d) isolated from wild-type (WT) or JAK3 knockout (KO) mice were allowed to migrate through a polycarbonate filter for 2 h toward IL-8 and MCP-1, respectively. The number of cells present in lower chamber was counted. Values are the mean±s.e.m. of three independent experiments (n=6 mice per group). *P<0.05, **P<0.01 vs vehicle; ##P<0.01 vs WT.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3674406&req=5

fig5: Effects of Janus-activated kinase 3 (JAK3) suppression on chemokine-directed cell migration. Neutrophils (a) and macrophages (b) that had been incubated with the indicated concentrations of JANEX-1 for 2 h were allowed to migrate through a polycarbonate filter for 2 h toward interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively. Neutrophils (c) and macrophages (d) isolated from wild-type (WT) or JAK3 knockout (KO) mice were allowed to migrate through a polycarbonate filter for 2 h toward IL-8 and MCP-1, respectively. The number of cells present in lower chamber was counted. Values are the mean±s.e.m. of three independent experiments (n=6 mice per group). *P<0.05, **P<0.01 vs vehicle; ##P<0.01 vs WT.
Mentions: To define the molecular mechanisms underlying JANEX-1-mediated inhibition of neutrophil and macrophage infiltration within the infarcted hearts, we isolated neutrophils and macrophages from mice and performed migration assay. Treatment of neutrophils with JANEX-1 inhibited the migration of these cells toward IL-8 in a concentration-dependent manner (Figure 5a). Similarly, macrophage migration toward MCP-1 was also effectively inhibited by JANEX-1 (Figure 5b). Neutrophils and macrophages isolated from JAK3 KO mice also showed decreased migration potential as compared with those cells isolated from normal mice (Figures 5c and d). These results suggest that in vivo JANEX-1-mediated inhibition of neutrophil and macrophage infiltration within the infarcted hearts was due to impaired migration potential of these cells.

Bottom Line: Treatment with JANEX-1 significantly decreased plasma creatine kinase and lactate dehydrogenase activities, reduced infarct size, reversed I/R-induced functional deterioration of the myocardium and reduced myocardial apoptosis.Histological analysis revealed an increase in neutrophil and macrophage infiltration within the infarcted area, which was markedly reduced by JANEX-1 treatment.Of note, however, JANEX-1 did not affect the expression of IL-8 and MCP-1 in the myocardium.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.

ABSTRACT
Recent studies have documented that Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathway can modulate the apoptotic program in a myocardial ischemia/reperfusion (I/R) model. To date, however, limited studies have examined the role of JAK3 on myocardial I/R injury. Here, we investigated the potential effects of pharmacological JAK3 inhibition with JANEX-1 in a myocardial I/R model. Mice were subjected to 45 min of ischemia followed by varying periods of reperfusion. JANEX-1 was injected 1 h before ischemia by intraperitoneal injection. Treatment with JANEX-1 significantly decreased plasma creatine kinase and lactate dehydrogenase activities, reduced infarct size, reversed I/R-induced functional deterioration of the myocardium and reduced myocardial apoptosis. Histological analysis revealed an increase in neutrophil and macrophage infiltration within the infarcted area, which was markedly reduced by JANEX-1 treatment. In parallel, in in vitro studies where neutrophils and macrophages were treated with JANEX-1 or isolated from JAK3 knockout mice, there was an impairment in the migration potential toward interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively. Of note, however, JANEX-1 did not affect the expression of IL-8 and MCP-1 in the myocardium. The pharmacological inhibition of JAK3 might represent an effective approach to reduce inflammation-mediated apoptotic damage initiated by myocardial I/R injury.

Show MeSH
Related in: MedlinePlus