Exp Mol Med.
2013 May;45(5):e23.
Inhibition of Janus activated kinase-3 protects against myocardial ischemia and reperfusion injury in mice
- Affiliations
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- 1Department of Physiology, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea. shkim@jbnu.ac.kr
- 2Department of Ophthalmology, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.
- 3Division of Biotechnology, College of Environmental and Bioresource Sciences, Chonbuk National University, Iksan, Jeonbuk, Republic of Korea.
- 4Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea. bhpark@jbnu.ac.kr
- 5Department of Internal Medicine, 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.
Keyword
MeSH Terms
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Animals
Apoptosis/drug effects
Cell Movement/drug effects
Chemokines/pharmacology
Heart Function Tests/drug effects
Inflammation/pathology
Janus Kinase 3/*antagonists & inhibitors/metabolism
Macrophages/drug effects/metabolism/pathology
Male
Mice
Mice, Inbred C57BL
Myocardial Reperfusion Injury/drug therapy/*enzymology/physiopathology/*prevention & control
Myocardium/enzymology/pathology
Myocytes, Cardiac/drug effects/metabolism/pathology
Neutrophils/drug effects/metabolism/pathology
Quinazolines/pharmacology/therapeutic use
Chemokines
Quinazolines
Janus Kinase 3
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