Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: pharmacotherapeutic implications.

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 [Ca(2+)] as a result of membrane depolarization-mediated opening of voltage-dependent Ca(2+) 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.

K+ channels in apoptosis.

A proper rate of programmed cell death or apoptosis is required to maintain normal tissue homeostasis. In disease states such as cancer and some forms of hypertension, apoptosis is blocked, resulting in hyperplasia. In neurodegenerative diseases, uncontrolled apoptosis leads to loss of brain tissue. The flow of ions in and out of the cell and its intracellular organelles is becoming increasingly linked to the generation of many of these diseased states. This review focuses on the transport of K(+) across the cell membrane and that of the mitochondria via integral K(+)-permeable channels. We describe the different types of K(+) channels that have been identified, and investigate the roles they play in controlling the different phases of apoptosis: early cell shrinkage, cytochrome c release, caspase activation, and DNA fragmentation. Attention is also given to K(+) channels on the inner mitochondrial membrane, whose activity may underlie anti- or pro-apoptotic mechanisms in neurons and cardiomyocytes.