Receptor tyrosine kinase profiling of ischemic heart identifies ROR1 as a potential therapeutic target

Show simple item record Heliste, Juho Jokilammi, Anne Paatero, Ilkka Chakroborty, Deepankar Stark, Christoffer Savunen, Timo Laaksonen, Maria Elenius, Klaus 2018-10-21T03:19:42Z 2018-10-21T03:19:42Z 2018-10-20
dc.identifier.citation BMC Cardiovascular Disorders. 2018 Oct 20;18(1):196
dc.description.abstract Abstract Background Receptor 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. Methods RTK 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. Results In 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. Conclusions Several 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.
dc.publisher BioMed Central
dc.subject Hypoxia
dc.subject Ischemic cardiomyopathy
dc.subject Myocardial ischemia
dc.subject Myocardial infarction
dc.subject Receptor tyrosine kinase
dc.title Receptor tyrosine kinase profiling of ischemic heart identifies ROR1 as a potential therapeutic target 2018-10-21T03:19:42Z
dc.language.rfc3066 en
dc.rights.holder The Author(s).

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