Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: pharmacotherapeutic implications
Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: pharmacotherapeutic implications
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DOI：
10.1038/sj.bjp.0707635
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发表时间：
2008-03-01
影响因子：
7.3
通讯作者：
Yuan, J. X-J
中科院分区：
文献类型：
--
作者：
Burg, E. D.;Remillard, C. V.;Yuan, J. X-J
维持细胞凋亡和增殖之间的适当平衡是正常组织稳态所必需的;当这种平衡被破坏时，可导致肺动脉高压（PAH）等疾病。K+通道的活性在调节肺血管系统中的肺动脉平滑肌细胞（PASMC）群体中起主要作用，因为它们参与细胞凋亡、存活和增殖。PAH患者的PASMCs表现出许多与K+通道相关的细胞异常，包括K+电流降低、各种K+通道表达下调和细胞凋亡抑制。K+是主要的细胞内阳离子，并且K+电流是细胞体积的主要决定因素。凋亡性容积减少（AVD）是细胞程序性死亡的早期标志和先决条件，其特征在于K+和Cl-外流。除了在AVD中的作用外，胞质K+还可抑制内源性半胱天冬酶和核酸酶，并可抑制线粒体细胞色素c释放。在PASMC中，K+通道激活加速AVD并促进凋亡，而K+通道抑制则减慢AVD并抑制凋亡。最后，由于膜去极化介导的电压依赖性Ca 2+通道开放，通过增加胞浆[Ca 2 +]抑制K+通道，导致PASMC收缩和增殖。本综述的目的有两个：（1）阐明K+离子和K+通道在PASMC增殖和凋亡中的作用，重点是PAH的人类和动物模型中的异常细胞生长，（2）阐述肺血管疾病药物治疗中K+通量途径的靶向作用。
Maintaining the proper balance between cell apoptosis and proliferation is required for normal tissue homeostasis; when this balance is disrupted, disease such as pulmonary arterial hypertension ( PAH) can result. Activity of K+ channels plays a major role in regulating the pulmonary artery smooth muscle cell ( PASMC) population in the pulmonary vasculature, as they are involved in cell apoptosis, survival and proliferation. PASMCs from PAH patients demonstrate many cellular abnormalities linked to K+ channels, including decreased K+ current, downregulated expression of various K+ channels, and inhibited apoptosis. K+ is the major intracellular cation, and the K+ current is a major determinant of cell volume. Apoptotic volume decrease (AVD), an early hallmark and prerequisite of programmed cell death, is characterized by K+ and Cl- efflux. In addition to its role in AVD, cytosolic K+ can be inhibitory toward endogenous caspases and nucleases and can suppress mitochondrial cytochrome c release. In PASMC, K+ channel activation accelerates AVD and enhances apoptosis, while K+ channel inhibition decelerates AVD and inhibits apoptosis. Finally, inhibition of K+ channels, by increasing cytosolic [Ca2+] as a result of membrane depolarization-mediated opening of voltage-dependent Ca2+ channels, leads to PASMC contraction and proliferation. The goals of this review are twofold: (1) to elucidate the role of K+ ions and K+ channels in the proliferation and apoptosis of PASMC, with an emphasis on abnormal cell growth in human and animal models of PAH, and ( 2) to elaborate upon the targeting of K+ flux pathways for pharmacological treatment of pulmonary vascular disease.