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.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…ANG II induces ET-1 expression by activation of c-Jun/c-Fos (AP1) and formation of chromatin remodeling complex that includes AP1-mediated recruitment of a histone H3K4 trimethyltransferase, either SET1 or MRTF-A (1138,1139,1222). Others report that endothelial tyrosine kinase Bmx and subsequent activation of STAT3 is necessary for ANG II-induced cardiac hypertrophy and fibrosis due to the induction of proinflammatory cytokines (389). ANG II stimulates cardiac fibroblasts to produce FGF-2, which is important for concentric hypertrophy and preventing dilated cardiomyopathy (810).…”

Hypoxia-induced upregulation of BMX kinase mediates therapeutic resistance in acute myeloid leukemia

“…Increased BMX expression was further confirmed by quantitative PCR (qPCR) analysis ( Figure 1B). BMX is a nonreceptor tyrosine kinase belonging to the Tec kinase family, which is highly expressed in myeloid and endothelial cells (11,12). BMX contains an SH2 domain that binds to tyrosine-phosphorylated proteins and a PH-like domain, which mediates membrane targeting by binding to phosphatidylinositol 3,4,5-triphosphate (PIP3) (13).…”

Nuclear localization of the tyrosine kinase BMX mediates VEGFR2 expression

“…The Vegfr2 gene promoter activities were significantly lower in HUVECs with BMX siRNA than in HUVECs with Ctrl siRNA, as determined by the luciferase activity assay (Figure B). Several studies have found that BMX tyrosine kinase activity has diverse functions under different conditions . Next, we assessed whether BMX kinase activity was required for Vegfr2 promoter activation by rendering BMX catalytically inactive by mutating its ATP co‐ordination site (K445R; Figure C).…”

“…In pathological cardiac hypertrophy development, inactivation of BMX abolished Ang II‐induced cardiac hypertrophy in mice. The effect of BMX on cardiac hypertrophy is mediated via the crosstalk between ECs of the coronary vasculature and cardiomyocytes . In another study, BMX kinase activity was found to be indispensable for IL‐8 promoter activation.…”