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Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling

Holopainen, Tanja and Räsänen, Markus and Anisimov, Andrey and Tuomainen, Tomi and Wei, Zheng and Tvogorov, Denis and Hulmi, Juha and Andersson, Leif and Cenni, Bruno and Tavi, Pasi and Mervaala, Eero and Kivelä, Riikka and Alitalo, Kari (2015) Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling. Proceedings of the National Academy of Sciences of the United States of America.

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.

Item Type: Article
Additional Information: Studz done under MTA 36157
Keywords: Bmx, Etk, nitric oxide, cardiac hypertrophy
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/10816

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