ABSTRACT
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0725
A fi ne balance between cell proliferation and apoptosis is critical to maintain normal tissue homeostasis. An imbalance in proliferative and apoptotic rates is the underlying pathophysiology of many disease states including cancer, neurodegenerative diseases and pulmonary vascular disease. Pulmonary arterial hypertension (PAH), for example, is a disease characterized by sustained elevated pulmonary vascular resistance and pulmonary arterial pressure. A contributory pathophysiological process is progressive pulmonary vascular remodeling, primarily due to an increased proliferative potential and decreased apoptotic rate in pulmonary artery smooth muscle cells in the medial layer of pulmonary arteries. A key hallmark of apoptosis is a two-phase cell shrinkage with apoptotic
volume decrease (AVD) being the early phase. Intracellular ion homeostasis, determined by the activity of plasma membrane ion channels and transporters, is the predominant mechanism regulating this early phase. During homeostasis cytoplasmic cation K+ (140 mM) and anion Cl-(~50-100 mM) concentration is high; this electrochemical gradient drives an effl ux of K+ upon opening of plasmalemmal K+ channels and initiates AVD. To equilibrate the imbalance created between intracellular and extracellular osmolarity with the extrusion of K+ and Cl-, water leaves the cell through aquaporins causing cell shrinkage. Th is early stage is a prerequisite for later phases of apoptosis including DNA fragmentation, caspase activation and mitochondrial membrane depolarization. Furthermore, the decreased intracellular K+ concentration relieves the inhibition of endogenous caspases and nucleases; nuclease induced chromatin fragmentation is able to occur. Finally, this leads to the formation and eventual phagocytosis of apoptotic bodies by macrophages. K+ channels have inherent roles in both the early and late phases of apoptosis. Th is chapter describes the involvement of K+ channels in apoptotic mechanisms, in particular as they pertain to pulmonary arterial hypertension.
