Nitric oxide as a bifunctional regulator of apoptosis.

Abstract

It was inevitable that important relationships between two of the most intensely studied topics in biomedical research, apoptosis and nitric oxide (NO), would become apparent. Apoptosis is essential to normal development as well as physiological cell turnover. Although apoptosis in excess can manifest as tissue damage, a failure to undergo apoptosis constitutes pathological cellular overgrowth. It is now evident that NO and its reaction products can either promote or prevent apoptosis in a multitude of settings. The ubiquitous distribution of the NO synthases and the remarkable diffusibility and diverse chemical reactivity of NO in biological systems make this molecule unique among the regulators of apoptosis. Understanding the factors that govern the consequences of NO exposure on cell viability and identifying the conditions in which NO regulation of apoptosis contribute to pathology are topics of considerable interest and potential importance. In this article, we will review the recent observations on NO as a regulator of apoptosis. Apoptosis, or programmed cell death, is distinguished from lytic or necrotic cell death by specific biochemical and structural events (see recent review in Reference 11 ). Apoptogenic signals trigger cell-specific signaling pathways, including protease activation, followed by the appearance of morphological changes characteristic of cells undergoing apoptosis, including condensation of nuclei and cytoplasm, blebbing of the cytoplasmic membranes, and finally fragmentation into apoptotic bodies that are phagocytosed by neighboring cells. The elucidation of the signaling events in apoptosis is occurring at a rapid pace and includes the identification of the key roles of cysteine proteases (known as caspases), Bcl-2 family members, and mitochondria. Caspases, the mammalian counterpart of ced-3 in Caenorhabditis elegans , are a family of cysteine proteases now known to contain at least 14 homologs. Ectopic expression of any of the caspase family proteases can cause apoptosis; however, not all caspase family …