title: Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling.
abstract: Cardiac hypertrophy accompanies many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease, and it is a strong predictor of increased cardiovascular morbidity and mortality. Deletion of bone marrow kinase in chromosome X (Bmx), an arterial nonreceptor tyrosine kinase, has been shown to inhibit cardiac hypertrophy in mice. This finding raised the possibility of therapeutic use of Bmx tyrosine kinase inhibitors, which we have addressed here by analyzing cardiac hypertrophy in gene-targeted mice deficient in Bmx tyrosine kinase activity. We found that angiotensin II (Ang II)-induced cardiac hypertrophy is significantly reduced in mice deficient in Bmx and in mice with inactivated Bmx tyrosine kinase compared with WT mice. Genome-wide transcriptomic profiling showed that Bmx inactivation suppresses myocardial expression of genes related to Ang II-induced inflammatory and extracellular matrix responses whereas expression of RNAs encoding mitochondrial proteins after Ang II administration was maintained in Bmx-inactivated hearts. Very little or no Bmx mRNA was expressed in human cardiomyocytes whereas human cardiac endothelial cells expressed abundant amounts. Ang II stimulation of endothelial cells increased Bmx phosphorylation, and Bmx gene silencing inhibited downstream STAT3 signaling, which has been implicated in cardiac hypertrophy. Furthermore, activation of the mechanistic target of rapamycin complex 1 pathway by Ang II treatment was decreased in the Bmx-deficient hearts. Our results demonstrate that inhibition of the cross-talk between endothelial cells and cardiomyocytes by Bmx inactivation suppresses Ang II-induced signals for cardiac hypertrophy. These results suggest that the endothelial Bmx tyrosine kinase could provide a target to attenuate the development of cardiac hypertrophy.
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland;
authors.forename: Tanja
authors.initials: T
authors.lastname: Holopainen
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland;
authors.forename: Markus
authors.initials: M
authors.lastname: Räsänen
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland;
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisimov
authors.affiliation: Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland;
authors.forename: Tomi
authors.initials: T
authors.lastname: Tuomainen
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland;
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland;
authors.forename: Denis
authors.initials: D
authors.lastname: Tvorogov
authors.affiliation: Department of Biology of Physical Activity, University of Jyväskylä, FI-40700 Jyväskylä, Finland;
authors.forename: Juha J
authors.initials: JJ
authors.lastname: Hulmi
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, FI-00014 Helsinki, Finland;
authors.forename: Leif C
authors.initials: LC
authors.lastname: Andersson
authors.affiliation: Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland;
authors.forename: Bruno
authors.initials: B
authors.lastname: Cenni
authors.affiliation: Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland;
authors.forename: Pasi
authors.initials: P
authors.lastname: Tavi
authors.affiliation: Department of Pharmacology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Mervaala
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland;
authors.forename: Riikka
authors.initials: R
authors.lastname: Kivelä
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland; kari.alitalo@helsinki.fi.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology*; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology*; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000201:enzymology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D000804:Angiotensin II; C492366:Bmx protein, mouse; D011505:Protein-Tyrosine Kinases
keywords: Etk; cardiomyocyte; endothelium; heart; signaling