磷酸二酯酶IV在心血管系统中的表达、活性及作用

Cyclic nucleotide phosphodiesterase IV expression,activity and targeting in cells of cardiovascular system

磷酸二酯酶(PDEs)催化水解细胞内第二信使cAMP及cGMP,使细胞内cAMP和cGMP呈浓度梯度及区室化分布,在信号传导和调控生理学反应中起中心作用,包括心血管系统在内的所有类型细胞的新陈代谢、收缩性、运动性和转录等。PDE4是cAMP特异性的水解酶,其水解活性通常占细胞内水解cAMP活性的绝大部分。近来的研究表明,PDE4在心血管系统的各种细胞类型上都有表达,在调控心血管系统的运动中有重要的作用,其表达和活性的改变与心衰和心律失常的发展有关。这些研究为开发治疗心血管疾病的药物提供了新的靶点。

Cyclic nucleotide second messages （cAMP and cGMP） play a central role in signal transduction and regulation of physiologic responses. The only way to inactivate them is to degrade them through the action of phosphodiesterases （PDEs）. Recent advances show that PDE4, a cAMP specific phosphodiesterase, has specific functions in regulating the activities of the cardiovascular system. PDE4 is expressed in the cells of cardiovascular systems including cardiomyocytes, vascular smooth muscle cells, and vascular endothelial cells. The expression level of PDE4 is shown to be downregulated in the failure hearts, while it is upregulated in hypertrophied hearts. And PDE4 deficiency in mice is associated with a cardiac phenotype comprised of a progressive, age-related cardiomyopathy, accelerated heart failure after myocardial infarction and exercise-induced arrhythmias. Local levels of cAMP regulate the precise opening of the ryanodine receptor complex （RyR2） which releases calcium at the start of a heartbeat. Loss or inhibition of PDE4 activity increases calcium flow through RyR2, and causes leakiness and heart failure in mice. These finding may show us a new target for treating cardiovascular diseases.