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首页> 外文期刊>Circulation research: a journal of the American Heart Association >Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy.
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Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy.

机译：Ca2 + /钙调蛋白刺激的环核苷酸磷酸二酯酶1在介导心肌肥大中的作用。

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RATIONALE: Cyclic nucleotide phosphodiesterases (PDEs) through the degradation of cGMP play critical roles in maintaining cardiomyocyte homeostasis. Ca(2+)/calmodulin (CaM)-activated cGMP-hydrolyzing PDE1 family may play a pivotal role in balancing intracellular Ca(2+)/CaM and cGMP signaling; however, its function in cardiomyocytes is unknown. OBJECTIVE: Herein, we investigate the role of Ca(2+)/CaM-stimulated PDE1 in regulating pathological cardiomyocyte hypertrophy in neonatal and adult rat ventricular myocytes and in the heart in vivo. METHODS AND RESULTS: Inhibition of PDE1 activity using a PDE1-selective inhibitor, IC86340, or downregulation of PDE1A using siRNA prevented phenylephrine induced pathological myocyte hypertrophy and hypertrophic marker expression in neonatal and adult rat ventricular myocytes. Importantly, administration of the PDE1 inhibitor IC86340 attenuated cardiac hypertrophy induced by chronic isoproterenol infusion in vivo. Both PDE1A and PDE1C mRNA and protein were detected in human hearts; however, PDE1A expression was conserved in rodent hearts. Moreover, PDE1A expression was significantly upregulated in vivo in the heart and myocytes from various pathological hypertrophy animal models and in vitro in isolated neonatal and adult rat ventricular myocytes treated with neurohumoral stimuli such as angiotensin II (Ang II) and isoproterenol. Furthermore, PDE1A plays a critical role in phenylephrine-induced reduction of intracellular cGMP- and cGMP-dependent protein kinase (PKG) activity and thereby cardiomyocyte hypertrophy in vitro. CONCLUSIONS: These results elucidate a novel role for Ca(2+)/CaM-stimulated PDE1, particularly PDE1A, in regulating pathological cardiomyocyte hypertrophy via a cGMP/PKG-dependent mechanism, thereby demonstrating Ca(2+) and cGMP signaling cross-talk during cardiac hypertrophy.
机译：理由：通过降解cGMP的环核苷酸磷酸二酯酶（PDE）在维持心肌细胞稳态方面起着关键作用。 Ca（2 +）/钙调蛋白（CaM）激活的cGMP水解PDE1家族可能在平衡细胞内Ca（2 +）/ CaM和cGMP信号传导中起关键作用;但是，其在心肌细胞中的功能尚不清楚。目的：在这里，我们调查的Ca（2 +）/ CaM刺激的PDE1在调节新生和成年大鼠心室肌细胞和体内心脏的病理性心肌肥大中的作用。方法和结果：使用PDE1选择性抑制剂IC86340抑制PDE1活性，或使用siRNA下调PDE1A可以防止去氧肾上腺素引起的病理性心肌肥大和肥大标志物在新生和成年大鼠心室肌细胞中的表达。重要的是，施用PDE1抑制剂IC86340可减轻体内慢性异丙肾上腺素输注引起的心脏肥大。在人的心脏中都检测到PDE1A和PDE1C mRNA和蛋白;然而，PDE1A表达在啮齿动物心脏中是保守的。此外，在各种病理性肥大动物模型的心脏和心肌细胞中，PDE1A的表达在体内显着上调;在用神经体液刺激物（如血管紧张素II（Ang II）和异丙肾上腺素）处理的分离的新生和成年大鼠心室心肌细胞中，PDE1A表达显着上调。此外，PDE1A在去氧肾上腺素诱导的细胞内cGMP和cGMP依赖性蛋白激酶（PKG）活性的降低，从而在体外心肌细胞肥大中起着关键作用。结论：这些结果阐明了Ca（2 +）/ CaM刺激的PDE1，特别是PDE1A，在通过cGMP / PKG依赖性机制调节病理性心肌肥大中的新颖作用，从而证明了Ca（2+）和cGMP信号的相互干扰在心脏肥大期间。

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