title: 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.
authors.affiliation: Department of Physiology, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Young-Bin
authors.initials: YB
authors.lastname: Oh
authors.forename: Min
authors.initials: M
authors.lastname: Ahn
authors.forename: Sang-Myeong
authors.initials: SM
authors.lastname: Lee
authors.forename: Hyoung-Won
authors.initials: HW
authors.lastname: Koh
authors.forename: Sun-Hwa
authors.initials: SH
authors.lastname: Lee
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000494:pharmacology; D006334:Heart Function Tests / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018925:Chemokines; D011799:Quinazolines; C116180:WHI P131; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3