Richard G. Frame; Gray Henderson; Bradford K. Chien; Evelyn G. Hazen
Abstract
Heart diseases remain the leading cause of death worldwide. The heart may suffer from ischemia due to several adverse clinical conditions, including myocardial infarction, arrhythmia, hypotension, cardiac arrest, or some cardiovascular surgical procedures. The extracellular signal-regulated kinase 5 (ERK5), also known as big MAPK 1, BMK1, or MAPK7, is a member of the mitogen-activated protein kinases (MAPKs) that plays a role in various cellular processes such as proliferation, differentiation, and survival. It has previously been reported that ERK5 could be activated by inflammatory stimuli and plays a positive regulatory role in TNF-α-induced MMP-9 expression in non-cardiac cells, while its role in cardiac cells and the heart during pathological conditions is still largely unknown. Moreover, its precise role in the context of myocardial I/R injury remains to be elucidated. The goal is to explore the functional role of ERK5 in TLR2-mediated inflammatory response, focusing on the upregulation of inflammatory mediator expression induced by global myocardial ischemia (GMI). The following specific aims were addressed: to examine the effect of GMI on the activation of ERK5 and the expression levels of inflammatory mediators in a cardiac model of GMI in vivo, as well as in neonatal rat ventricular myocytes (NRVM) treated with GMI in vitro; to investigate the role of ERK5 activation in the upregulation of inflammatory mediator expression induced by GMI in vitro; and to clarify the molecular mechanism underlying the role of ERK5 in the GMI-induced inflammatory response. The findings indicate that ERK5 activation is involved in the upregulation of TLR2-dependent inflammatory mediator expression in response to GMI, which may provide insight into the development of new therapeutic strategies to treat I/R injury.
Keywords: Global myocardial ischemia and reperfusion; TLR2; ERK5; siRNA knockdown
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