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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B
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Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

机译：表达利钠肽受体B显性负突变的转基因大鼠的心脏肥大

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摘要

Natriuretic peptides (NP) 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 antiprolif-erative and antihypertrophic 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-BΔKC) 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-BΔKC expression selectively reduced NPR-B but not NPR-A signaling. NPR-BΔKC 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.
机译：利钠肽（NP）通过激活与膜结合的鸟苷酸环化酶偶联受体A（NPR-A）或B（NPR-B）来介导其作用。尽管已经广泛研究了NPR-A的病理生理作用，但是仅可获得关于NPR-B的心血管功能的有限知识。体外研究表明，NPR-B配体C型NP（CNP）具有抗增殖和抗肥大的作用。由于缺少特定的药理抑制剂，这些作用不能明确归因于NPR-B信号传导受损。最近，基因删除揭示了NPR-B在软骨内骨化和女性生殖器官发育中的主要作用。但是，NPR-B缺陷型小鼠的形态异常和过早死亡无法进行详细的心血管表型分析。在本研究中，显性阴性突变体（NPR-BΔKC）用于表征体外和转基因大鼠中依赖CNP的NPR-B信号传导。在这里，我们证明减少的CNP，但不是心房NP依赖的cGMP反应减弱了CNP在体外的抗肥力。在转基因大鼠中，NPR-BΔKC表达选择性降低NPR-B，但不降低NPR-A信号传导。 NPR-BΔKC转基因大鼠表现出进行性，与血压无关的心脏肥大和心率升高。在慢性容量超负荷引起的充血性心力衰竭中，肥大表型进一步增强。因此，这项研究提供了将NPR-B信号传导与心脏生长控制联系起来的证据。

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