Inhibition of Janus activated kinase-3 protects against myocardial ischemia and reperfusion injury in mice.
- Author:
Young Bin OH
1
;
Min AHN
;
Sang Myeong LEE
;
Hyoung Won KOH
;
Sun Hwa LEE
;
Suhn Hee KIM
;
Byung Hyun PARK
Author Information
1. Department of Physiology, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea. shkim@jbnu.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
apoptosis;
infiltration;
ischemia/reperfusion;
JAK3;
JANEX-1
- MeSH:
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
- From:Experimental & Molecular Medicine
2013;45(5):e23-
- CountryRepublic of Korea
- Language:English
-
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.
