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.
Highlights
Myocardial ischemia/reperfusion (I/R) injury is currently the leading cause of death worldwide.[1]
Serum levels of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) were significantly increased in mice subjected to I/R injury compared with sham-operated mice (Figure 1a)
This study was designed to elucidate the potential effects of JAK3 suppression on myocardial I/R injury
Summary
Myocardial ischemia/reperfusion (I/R) injury is currently the leading cause of death worldwide.[1] A number of mechanisms have been postulated to contribute to the myocardial damage caused by I/R injury such as ion accumulation, dissipation of mitochondrial membrane potential, free radical formation, nitric oxide metabolism, apoptosis and autophagy, endothelial dysfunction and immune activation.[2] the understanding of I/R injury is still far from complete. Experimental studies performed in animal models of myocardial infarction have shown that infiltrated inflammatory cells play a key role in the extension of myocardial tissue injury and lead to adverse effects during recovery.[3,4] crucial to healing, the infiltration of macrophage and neutrophil results in tissue injury beyond that caused by ischemia alone. Neutrophil infiltration into ischemic tissue increases tissue necrosis by releasing reactive oxygen species and proteolytic enzymes and expand the infarct area.[6]
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