Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B
Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B
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DOI：
10.1073/pnas.0510019103
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发表时间：
2006-03-21
影响因子：
11.1
通讯作者：
Bader, M
中科院分区：
文献类型：
--
作者：
Langenickel, TH;Buttgereit, J;Bader, M
利钠肽（NIP）通过激活膜结合的胍基环化酶偶联受体A （NPR-A）或B （NPR-B）介导其作用。尽管人们对NPR-A的病理生理作用进行了广泛的研究，但对NPR-B的心血管功能了解有限。体外研究表明，NPR-B配体c型NP （CNP）具有抗增殖和抗肥厚作用。由于缺乏特定的药理学抑制剂，这些影响不能明确归因于受损的NPR-B信号。最近，基因缺失揭示了NPR-B在女性生殖器官软骨内成骨和发育中的主导作用。然而，形态异常和过早死亡的npr - b缺陷小鼠排除了详细的心血管表型。在本研究中，利用显性阴性突变体（NPR-B Delta KC）在体外和转基因大鼠中表征cnp依赖性NPR-B信号传导。在这里，我们证明减少CNP-而不是心房np依赖的cGMP反应在体外减弱CNP的抗肥厚效力。在转基因大鼠中，NPR-B δ KC的表达选择性地减少了NPR-B而不是NPR-A信号传导。NPR-B Delta KC转基因大鼠表现出进行性、不依赖血压的心肌肥厚和心率升高。在慢性容量超载引起的充血性心力衰竭中，肥厚表型进一步增强。因此，本研究提供了将NPR-B信号与心脏生长控制联系起来的证据。
Natriuretic peptides (NIP) mediate their effects by activating membrane-bound guanylyl cyclase-coupled receptors A (NPR-A) or B (NPR-B). Whereas the pathophysiological role of NPR-A has been widely studied, only limited knowledge on the cardiovascular function of NPR-B is available. In vitro studies suggest antiproliferative and anti hypertrophic actions of the NPR-B ligand C-type NP (CNP). Because of the lack of a specific pharmacological inhibitor, these effects could not clearly be attributed to impaired NPR-B signaling. Recently, gene deletion revealed a predominant role of NPR-B in endochondral ossification and development of female reproductive organs. However, morphological abnormalities and premature death of NPR-B-deficient mice preclude detailed cardiovascular phenotyping. In the present study, a dominant-negative mutant (NPR-B Delta KC) was used to characterize CNP-dependent NPR-B signaling in vitro and in transgenic rats. Here we demonstrate that reduced CNP- but not atrial NP-dependent cGMP response attenuates antihypertrophic potency of CNP in vitro. In transgenic rats, NPR-B Delta KC expression selectively reduced NPR-B but not NPR-A signaling. NPR-B Delta KC transgenic rats display progressive, blood pressure-independent cardiac hypertrophy and elevated heart rate. The hypertrophic phenotype is further enhanced in chronic volume overload-induced congestive heart failure. Thus, this study provides evidence linking NPR-B signaling to the control of cardiac growth.