Abstract
BackgroundReceptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. The human RTK family consists of 55 members, most of which have not yet been characterized for expression or activity in the ischemic heart.MethodsRTK gene expression was analyzed from human heart samples representing healthy tissue, acute myocardial infarction or ischemic cardiomyopathy. As an experimental model, pig heart with ischemia-reperfusion injury, caused by cardiopulmonary bypass, was used, from which phosphorylation status of RTKs was assessed with a phospho-RTK array. Expression and function of one RTK, ROR1, was further validated in pig tissue samples, and in HL-1 cardiomyocytes and H9c2 cardiomyoblasts, exposed to hypoxia and reoxygenation. ROR1 protein level was analyzed by Western blotting. Cell viability after ROR1 siRNA knockdown or activation with Wnt-5a ligand was assessed by MTT assays.ResultsIn addition to previously characterized RTKs, a group of novel active and regulated RTKs was detected in the ischemic heart. ROR1 was the most significantly upregulated RTK in human ischemic cardiomyopathy. However, ROR1 phosphorylation was suppressed in the pig model of ischemia-reperfusion and ROR1 phosphorylation and expression were down-regulated in HL-1 cardiomyocytes subjected to short-term hypoxia in vitro. ROR1 expression in the pig heart was confirmed on protein and mRNA level. Functionally, ROR1 activity was associated with reduced viability of HL-1 cardiomyocytes in both normoxia and during hypoxia-reoxygenation.ConclusionsSeveral novel RTKs were found to be regulated in expression or activity in ischemic heart. ROR1 was one of the most significantly regulated RTKs. The in vitro findings suggest a role for ROR1 as a potential target for the treatment of ischemic heart injury.
Highlights
Receptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease
Expression of EGFR and ERBB2 have been demonstrated to be regulated in infarcted human heart [8, 9], and alterations in EGFR, ERBB2, ERBB4, VEGFR1, VEGFR2, IGF1R, Heliste et al BMC Cardiovascular Disorders (2018) 18:196 and INSR signaling have been observed in experimental ischemia-reperfusion models [8, 10,11,12]
Out of the 55 RTKs listed by HUGO Gene Nomenclature Committee, data were available for 49 genes in acute myocardial infarction samples and for 52 genes in ischemic cardiomyopathy samples (Additional file 1)
Summary
Receptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. A few RTKs have been shown to be necessary for development of the heart in gene-modified mouse models. Such examples include Erbb2 [3, 4], Erbb4 [5], Ror1 [6], and Ror2 [6, 7]. Expression of EGFR and ERBB2 have been demonstrated to be regulated in infarcted human heart [8, 9], and alterations in EGFR, ERBB2, ERBB4, VEGFR1, VEGFR2, IGF1R, Heliste et al BMC Cardiovascular Disorders (2018) 18:196 and INSR signaling have been observed in experimental ischemia-reperfusion models [8, 10,11,12]
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