Key result
Inactivating Bmx tyrosine kinase reduces Ang II-induced cardiac hypertrophy in mice.
Why the study?
Cardiac hypertrophy is a strong predictor of cardiovascular morbidity and mortality, and the role of endothelial Bmx tyrosine kinase in myocardial hypertrophy and remodeling was unclear.
Does Bmx tyrosine kinase inactivation prevent Ang II-induced cardiac hypertrophy in mice?
Does Bmx tyrosine kinase inactivation prevent Ang II-induced cardiac hypertrophy in mice?
Inactivation of endothelial Bmx tyrosine kinase suppresses Ang II-induced cardiac hypertrophy, highlighting it as a potential therapeutic target.
Supports Bmx inhibition as a hypertrophy target in mice; leaves open clinical translation of kinase inhibitors.
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.
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Holopainen et al. (2015) studied Cardiac hypertrophy. Bmx tyrosine kinase inactivation vs. Wild-type mice was evaluated on Angiotensin II-induced cardiac hypertrophy. Inactivation of Bmx tyrosine kinase significantly reduced angiotensin II-induced cardiac hypertrophy in mice compared with wild-type mice.