Integrin-linked kinase, a novel component of the cardiac mechanical stretch sensor, controls contractility in the zebrafish heart
Integrin-linked kinase, a novel component of the cardiac mechanical stretch sensor, controls contractility in the zebrafish heart
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DOI：
10.1101/gad.1448306
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发表时间：
2006-09-01
影响因子：
10.5
通讯作者：
Rottbauer, Wolfgang
中科院分区：
文献类型：
--
作者：
Bendig, Garnet;Grimmler, Matthias;Rottbauer, Wolfgang
脊椎动物的心脏具有自动调节机制，使其能够首先感知，然后根据不断变化的需求调整其收缩力。心脏机械牵张传感器的分子组分大多是未知的，但具有巨大的医学重要性，因为这种传感机制的功能障碍被怀疑是造成人类心力衰竭的重要原因。在乙基亚硝基脲（ENU）诱导的隐性胚胎致死性斑马鱼心力衰竭突变体主挤压（msq）的心脏中，我们发现牵张反应基因如心房利钠因子（anf）和血管内皮生长因子（vegf）严重下调。我们通过定位克隆证明msq突变体的心力衰竭是由于整合素连接激酶（ilk）基因突变引起的。ILK特异性定位于肋肌和肌节Z盘。msq突变（L308 P）降低ILK激酶活性并破坏ILK与Z盘衔接蛋白β-小粘蛋白（粘附素）的结合。因此，在msq突变胚胎中，心力衰竭可以通过ILK以及蛋白激酶B（PK B）和VEGF的组成型活性形式的表达来抑制。此外，反义介导的斑马鱼β-parvin表型的废除模仿msq表型。因此，我们提供的证据表明，心脏使用整合素-ILK-β-parvin网络来感知机械拉伸，并以ANF和VEGF的表达增加来响应，后者最近被证明通过增加心脏的钙瞬变来增加心力。
The vertebrate heart possesses autoregulatory mechanisms enabling it first to sense and then to adapt its force of contraction to continually changing demands. The molecular components of the cardiac mechanical stretch sensor are mostly unknown but of immense medical importance, since dysfunction of this sensing machinery is suspected to be responsible for a significant proportion of human heart failure. In the hearts of the ethylnitros-urea (ENU)- induced, recessive embryonic lethal zebrafish heart failure mutant main squeeze (msq), we find stretch- responsive genes such as atrial natriuretic factor (anf) and vascular endothelial growth factor (vegf) severely down-regulated. We demonstrate through positional cloning that heart failure in msq mutants is due to a mutation in the integrin-linked kinase (ilk) gene. ILK specifically localizes to costameres and sarcomeric Z-discs. The msq mutation (L308P) reduces ILK kinase activity and disrupts binding of ILK to the Z- disc adaptor protein beta-parvin (Affixin). Accordingly, in msq mutant embryos, heart failure can be suppressed by expression of ILK, and also of a constitutively active form of Protein Kinase B (PKB), and VEGF. Furthermore, antisense- mediated abrogation of zebrafish beta-parvin phenocopies the msq phenotype. Thus, we provide evidence that the heart uses the Integrin-ILK-beta-parvin network to sense mechanical stretch and respond with increased expression of ANF and VEGF, the latter of which was recently shown to augment cardiac force by increasing the heart's calcium transients.