Cytoskeletal role in protection of the failing heart by β-adrenergic blockade
Cytoskeletal role in protection of the failing heart by β-adrenergic blockade
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DOI：
10.1152/ajpheart.00867.2011
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发表时间：
2012-02-01
影响因子：
4.8
通讯作者：
Cooper, George
中科院分区：
文献类型：
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作者：
Cheng, Guangmao;Kasiganesan, Harinath;Cooper, George
程G，卡西加内森H，白楚，瓦伦博恩，库普斯瓦米D，库珀G第四。细胞骨架在β-肾上腺素受体阻滞剂保护衰竭心脏中的作用。Am J Physiol心脏圈Physiol 302：H675-H687,2012。2011年11月11日首次出版；DOI：10.1152/ajpheart.00867.2011。-在严重的压力超负荷肥厚中形成致密的微管网络，阻碍心脏收缩和细胞内运输。这个过程是高度动态的，因为微管解聚导致收缩功能的显著改善。这种细胞骨架改变的分子病因学被定义为主要的心肌微管相关蛋白(MAP)4的1型和2A型磷酸酶依赖的位点特异性去磷酸化，然后修饰和稳定微管。这种持续的磷酸酶激活依赖于p21激活的激酶-1，或pak1的持续上游活性。由于在失代偿性肥厚时，心脏β-肾上腺素能活性显著且持续增强，并且已经证实心脏蛋白1和磷酸酶的β-肾上腺素能激活，我们在这里询问病理性肥厚中出现的高度不适应的心脏微管表型是否基于β-肾上腺素能过度驱动，从而可以被β-肾上腺素能阻断而逆转。这项研究中的数据，旨在回答这个问题，表明情况是这样的；即，β(1)-(但不是β(2)-)肾上腺素能激活这一途径，该途径包括Ak1激活，磷酸酶活性增加，MAP4去磷酸化，从而稳定致密的微管网络。这些数据是在一只猫右室(RV)压力超负荷肥厚的猫模型中收集的，该模型是对紧密的肺动脉环扎(PAB)的反应，在该模型中，在压力超负荷后2周，RV质量稳定地增加了两倍。在肥大诱导2wk后，这些PAB猫在接下来的2wk内要么不再接受进一步治疗，要么被β-肾上腺素能阻断。病理微管表型和严重的RV细胞收缩功能障碍，在这种RV肥厚模型(PAB未治疗)中被治疗(PABβ-阻滞剂)猫逆转。因此，这些数据为某些形式的病理性心肌肥厚中发现的异常微管网络提供了特定的病因和特定的治疗方法。
Cheng G, Kasiganesan H, Baicu CF, Wallenborn JG, Kuppuswamy D, Cooper G 4th. Cytoskeletal role in protection of the failing heart by beta-adrenergic blockade. Am J Physiol Heart Circ Physiol 302: H675-H687, 2012. First published November 11, 2011; doi:10.1152/ajpheart.00867.2011.-Formation of a dense microtubule network that impedes cardiac contraction and intracellular transport occurs in severe pressure overload hypertrophy. This process is highly dynamic, since microtubule depolymerization causes striking improvement in contractile function. A molecular etiology for this cytoskeletal alteration has been defined in terms of type 1 and type 2A phosphatase-dependent site-specific dephosphorylation of the predominant myocardial microtubule-associated protein (MAP) 4, which then decorates and stabilizes microtubules. This persistent phosphatase activation is dependent upon ongoing upstream activity of p21-activated kinase-1, or Pak1. Because cardiac beta-adrenergic activity is markedly and continuously increased in decompensated hypertrophy, and because beta-adrenergic activation of cardiac Pak1 and phosphatases has been demonstrated, we asked here whether the highly maladaptive cardiac microtubule phenotype seen in pathological hypertrophy is based on beta-adrenergic overdrive and thus could be reversed by beta-adrenergic blockade. The data in this study, which were designed to answer this question, show that such is the case; that is, beta(1)-(but not beta(2)-) adrenergic input activates this pathway, which consists of Pak1 activation, increased phosphatase activity, MAP4 dephosphorylation, and thus the stabilization of a dense microtubule network. These data were gathered in a feline model of severe right ventricular (RV) pressure overload hypertrophy in response to tight pulmonary artery banding (PAB) in which a stable, twofold increase in RV mass is reached by 2 wk after pressure overloading. After 2 wk of hypertrophy induction, these PAB cats during the following 2 wk either had no further treatment or had beta-adrenergic blockade. The pathological microtubule phenotype and the severe RV cellular contractile dysfunction otherwise seen in this model of RV hypertrophy (PAB No Treatment) was reversed in the treated (PAB beta-Blockade) cats. Thus these data provide both a specific etiology and a specific remedy for the abnormal microtubule network found in some forms of pathological cardiac hypertrophy.