Cyclic nucleotide phosphodiesterase 1 regulates lysosome-dependent type I collagen protein degradation in vascular smooth muscle cells.
Cyclic nucleotide phosphodiesterase 1 regulates lysosome-dependent type I collagen protein degradation in vascular smooth muscle cells.
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DOI：
10.1161/atvbaha.110.212621
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发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
Yan C
中科院分区：
文献类型：
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作者：
Cai Y;Miller CL;Nagel DJ;Jeon KI;Lim S;Gao P;Knight PA;Yan C
血管平滑肌细胞(VSMCs)表型向合成表型的转化在病理性血管重塑和各种血管疾病的发生发展过程中起着至关重要的作用。I型胶原(I型胶原)的增加与合成的VSMC有关，而环核苷酸信号在I型胶原的调节中起着关键作用。在此，我们研究了环核苷酸磷酸二酯酶1(PDE1)在合成的VSMC中调节I型胶原的作用及其机制。PDE1抑制剂IC86340可显著降低体外培养人大隐静脉自发性重塑过程中的I型胶原。IC86340可显著降低合成的VSMCs细胞内和细胞外高基础水平的I型胶原蛋白。这种衰减是由于蛋白质的减少，而不是mRNA的减少。抑制溶酶体功能可阻断IC86340对I型胶原蛋白表达的影响。PDE1C而不是PDE1a是介导IC86340作用的主要异构体。PDE1C调控对碳酸氢盐敏感的可溶性腺苷环化酶/cAMP信号转导通路，在VSMC降解I型胶原过程中起关键作用。这些结果表明，PDE1C调节可溶性腺苷环化酶/cAMP信号转导和溶酶体介导的I型胶原蛋白降解，提示PDE1C在病理性血管重塑过程中调节胶原动态平衡起关键作用。
The phenotypic modulation of vascular smooth muscle cells (VSMCs) to a synthetic phenotype is vital during pathological vascular remodeling and the development of various vascular diseases. An increase in type I collagen (collagen I) has been implicated in synthetic VSMCs, and cyclic nucleotide signaling is critical in collagen I regulation. Herein, we investigate the role and underlying mechanism of cyclic nucleotide phosphodiesterase 1 (PDE1) in regulating collagen I in synthetic VSMCs. The PDE1 inhibitor IC86340 significantly reduced collagen I in human saphenous vein explants undergoing spontaneous remodeling via ex vivo culture. In synthetic VSMCs, high basal levels of intracellular and extracellular collagen I protein were markedly decreased by IC86340. This attenuation was due to diminished protein but not mRNA. Inhibition of lysosome function abolished the effect of IC86340 on collagen I protein expression. PDE1C but not PDE1A is the major isoform responsible for mediating the effects of IC86340. Bicarbonate-sensitive soluble adenylyl cyclase/cAMP signaling was modulated by PDE1C, which is critical in collagen I degradation in VSMCs. These data demonstrate that PDE1C regulates soluble adenylyl cyclase/cAMP signaling and lysosome-mediated collagen I protein degradation, and they suggest that PDE1C plays a critical role in regulating collagen homeostasis during pathological vascular remodeling.