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

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.

Alamandine Protects the Heart Against Reperfusion Injury via the MrgD Receptor

“…These results support earlier reports showing cardioprotection with reduced apoptosis after I/R. 16,17,23,33 Interestingly, the amounts of ANP in the coronary effluent of in vitro I/R hearts and in the plasma of in vivo I/R rats were significantly higher in alamandine-treated groups than in the control groups. These results suggest that alamandine may increase ANP secretion.…”

Triptolide Attenuates Myocardial Ischemia/Reperfusion Injuries in Rats by Inducing the Activation of Nrf2/HO-1 Defense Pathway

“…Enhanced macrophage infiltration in myocardium commonly occurs during I/R injury as revealed by our study and several previous studies [29]. Pro-inflammatory cytokines TNF-a, IL-1b and IL-6 are released by activated macrophages, monocytes, lymphocytes and many other cell types, the overproduction of which appears to exacerbate I/R injury [30,31].…”

Interleukin-37 ameliorates myocardial ischaemia/reperfusion injury in mice

“…Neutrophils were isolated from the marrow of femurs and tibias of adult C57BL/6 mice, as described previously . The mice were anaesthetized by an intraperitoneal injection of pentobarbital sodium (50 mg/kg) before euthanasia by cervical dislocation.…”