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 [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.