Holopainen Tanja, Räsänen Markus, Anisimov Andrey, Tuomainen Tomi, Zheng Wei, Tvorogov Denis, Hulmi Juha J, Andersson Leif C, Cenni Bruno, Tavi Pasi, Mervaala Eero, Kivelä Riikka, Alitalo Kari
Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland;
Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland;
Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):13063-8. doi: 10.1073/pnas.1517810112. Epub 2015 Oct 1.
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.
心脏肥大伴随多种形式的心脏病，包括缺血性疾病、高血压、心力衰竭和瓣膜疾病，并且是心血管发病率和死亡率增加的有力预测指标。X染色体骨髓激酶（Bmx）是一种动脉非受体酪氨酸激酶，其缺失已被证明可抑制小鼠的心脏肥大。这一发现增加了Bmx酪氨酸激酶抑制剂治疗用途的可能性，我们通过分析缺乏Bmx酪氨酸激酶活性的基因靶向小鼠的心脏肥大来解决这一问题。我们发现，与野生型小鼠相比，Bmx缺陷小鼠和Bmx酪氨酸激酶失活的小鼠中，血管紧张素II（Ang II）诱导的心脏肥大显著减少。全基因组转录组分析表明，Bmx失活抑制了与Ang II诱导的炎症和细胞外基质反应相关的心肌基因表达，而在Bmx失活的心脏中，Ang II给药后编码线粒体蛋白的RNA表达得以维持。人心肌细胞中几乎不表达或不表达Bmx mRNA，而人心脏内皮细胞表达大量Bmx mRNA。Ang II刺激内皮细胞可增加Bmx磷酸化，Bmx基因沉默可抑制下游STAT3信号传导，而STAT3信号传导与心脏肥大有关。此外，在Bmx缺陷的心脏中，Ang II处理对雷帕霉素复合物1机制靶点通路的激活作用降低。我们的结果表明，Bmx失活抑制内皮细胞与心肌细胞之间的相互作用，从而抑制Ang II诱导的心脏肥大信号。这些结果表明，内皮Bmx酪氨酸激酶可能成为减轻心脏肥大发展的靶点。
