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

  1. Kari Alitaloa,1,2
  1. aWihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland;
  2. bDepartment of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland;
  3. cDepartment of Biology of Physical Activity, University of Jyväskylä, FI-40700 Jyväskylä, Finland;
  4. dDepartment of Pathology, Haartman Institute, University of Helsinki, FI-00014 Helsinki, Finland;
  5. eNovartis Institutes for Biomedical Research, Basel CH-4002, Switzerland;
  6. fDepartment of Pharmacology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, FI-00014 Helsinki, Finland

  1. Contributed by Kari Alitalo, September 8, 2015 (sent for review May 13, 2015; reviewed by Bernd Groner and Christian Kupatt)

Significance

During the last decades, heart failure has developed into a major burden in the western world, increasingly affecting millions. Cardiac hypertrophy is an adaptive response to myocardial infarction or increased blood pressure, and it often leads to heart failure. Understanding the underlying regulatory processes in the development of pathological hypertrophy is needed for the development of effective therapies. Our results show that the kinase activity of the endothelial bone marrow kinase in chromosome X (Bmx) protein is necessary for the development of pathological cardiac hypertrophy. This finding could provide significant therapeutic applications when specific Bmx kinase inhibitors become available in the clinics.

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.

Footnotes

  • ↵1R.K. and K.A. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: kari.alitalo{at}helsinki.fi.

  • Author contributions: T.H., P.T., E.M., R.K., and K.A. designed research; T.H., M.R., A.A., T.T., W.Z., D.T., J.J.H., and R.K. performed research; T.T., B.C., P.T., and E.M. contributed new reagents/analytic tools; T.H., M.R., J.J.H., L.C.A., E.M., R.K., and K.A. analyzed data; and T.H., R.K., and K.A. wrote the paper.

  • Reviewers: B.G., Georg Speyer Haus; and C.K., Klinikum Grosshadern Munich.

  • Conflict of interest statement: B.C. is an employee of Novartis.

  • Data deposition: The microarray data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE47420).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1517810112/-/DCSupplemental.

Freely available online through the PNAS open access option.

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