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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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Related in: MedlinePlus

Measurement of myocardial injury. (a) Mice underwent 45 min of myocardial ischemia and 24 h of reperfusion, and serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) were analyzed. (b) Representative photographs of the infarcted hearts are shown. (c) Results are percentage of infarct size relative to area at risk. Values are the mean±s.e.m. of four independent experiments (n=8–13 mice per group). **P<0.01 vs sham; #P<0.05, ##P<0.01 vs ischemia/reperfusion (I/R)-operated wild-type (WT) mice.
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fig1: Measurement of myocardial injury. (a) Mice underwent 45 min of myocardial ischemia and 24 h of reperfusion, and serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) were analyzed. (b) Representative photographs of the infarcted hearts are shown. (c) Results are percentage of infarct size relative to area at risk. Values are the mean±s.e.m. of four independent experiments (n=8–13 mice per group). **P<0.01 vs sham; #P<0.05, ##P<0.01 vs ischemia/reperfusion (I/R)-operated wild-type (WT) mice.

Mentions: After 45 min of ischemia, varying periods of reperfusion injury were given to mice and myocardial injury was evaluated (Supplementary Figure S1). Serum levels of CPK and LDH were significantly increased in mice subjected to I/R injury compared with sham-operated mice (Figure 1a). JANEX-1 was administered at doses ranging from 5 to 100 mg kg−1. Evaluation of CPK activity revealed a dose-response curve with an effective dose 50 (ED50) value of 7.44 mg kg−1 (Supplementary Figure S2). Mice receiving JANEX-1 displayed significantly reduced CPK and LDH levels. In addition, the infarct size of JANEX-1-treated mice (30.16±2.79%) was significantly decreased when compared with I/R-operated mice (65.64±3.76% Figures 1b and c).


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)

Measurement of myocardial injury. (a) Mice underwent 45 min of myocardial ischemia and 24 h of reperfusion, and serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) were analyzed. (b) Representative photographs of the infarcted hearts are shown. (c) Results are percentage of infarct size relative to area at risk. Values are the mean±s.e.m. of four independent experiments (n=8–13 mice per group). **P<0.01 vs sham; #P<0.05, ##P<0.01 vs ischemia/reperfusion (I/R)-operated wild-type (WT) mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Measurement of myocardial injury. (a) Mice underwent 45 min of myocardial ischemia and 24 h of reperfusion, and serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) were analyzed. (b) Representative photographs of the infarcted hearts are shown. (c) Results are percentage of infarct size relative to area at risk. Values are the mean±s.e.m. of four independent experiments (n=8–13 mice per group). **P<0.01 vs sham; #P<0.05, ##P<0.01 vs ischemia/reperfusion (I/R)-operated wild-type (WT) mice.
Mentions: After 45 min of ischemia, varying periods of reperfusion injury were given to mice and myocardial injury was evaluated (Supplementary Figure S1). Serum levels of CPK and LDH were significantly increased in mice subjected to I/R injury compared with sham-operated mice (Figure 1a). JANEX-1 was administered at doses ranging from 5 to 100 mg kg−1. Evaluation of CPK activity revealed a dose-response curve with an effective dose 50 (ED50) value of 7.44 mg kg−1 (Supplementary Figure S2). Mice receiving JANEX-1 displayed significantly reduced CPK and LDH levels. In addition, the infarct size of JANEX-1-treated mice (30.16±2.79%) was significantly decreased when compared with I/R-operated mice (65.64±3.76% Figures 1b and c).

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