Nitric oxide inhibits stress-induced endothelial cell apoptosis
- 1 September 1998
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Critical Care Medicine
- Vol. 26 (9), 1500-1509
- https://doi.org/10.1097/00003246-199809000-00016
Abstract
To determine a mechanism by which nitric oxide alters induction of stress-induced endothelial cell apoptosis in vitro. Apoptosis is a form of cellular suicide that has been implicated in the pathogenesis of multiple organ dysfunction syndrome. Prospective, controlled trial. Research laboratory of a large, academic medical center. Cultured primary porcine aortic endothelial cells. Cells were treated with a range of doses of agents that either spontaneously generate nitric oxide (S-nitroso-N-acetyl-D,L-penicillamine [SNAP] or (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1,2-diolate [DETA-NO]) or block nitric oxide production (Nomega-methyl-L-arginine [L-NMA]). The ability of these agents to alter the rate of cell death by apoptosis (induced by the sequence stimuli lipopolysaccharide [LPS] followed by sodium arsenite) was measured. Mechanistic studies included examining the ability of: a) nitric oxide "donors" to alter nuclear factor kappa B (NF-kappaB) DNA binding activity and the level of IkappaBalpha accumulation; and b) a stable cyclic guanosine monophosphate (cGMP) analog (8-bromo-cGMP) to mimic the effect of nitric oxide donors. The sequence LPS/sodium arsenite increased the rate of endothelial cell apoptosis (47.4%, p< .05 vs. control), as measured by fluorescent-activated cell scanning using annexin V/propidium iodide staining. DETA-NO generated nitric oxide (as indicated by an increase in the concentration of the stable end-products of nitric oxide metabolism) and decreased the rate of endothelial cell apoptosis (20.6% at a dose of 2 mM, p=.0001 vs. control). DETA-NO also decreased NF-kappaB DNA binding activity and the apparent accumulation of its endogenous inhibitor, IkappaBalpha. The 8-bromo-cGMP did not mimic the effects of nitric oxide donors (DETA-NO) on apoptosis. These data suggest that exogenous nitric oxide can block stress-induced endothelial cell apoptosis in vitro. The mechanistic studies are consistent with our hypothesis that inhibitors of NF-kappaB DNA binding activity are associated with protection against apoptosis-inducing stimuli. The results do not support a role for cGMP in mediating the protective effect of DETA-NO in our model.Keywords
This publication has 36 references indexed in Scilit:
- Apoptosis in lymphoid and parenchymal cells during sepsisCritical Care Medicine, 1997
- Apoptosis by Death FactorCell, 1997
- Mechanisms of cell injury and deathBritish Journal of Anaesthesia, 1996
- Toward a theory regarding the pathogenesis of the systemic inflammatory response syndromeCritical Care Medicine, 1996
- HEAT SHOCK-INDUCED CELL DEATH IN MURINE MICROVASCULAR ENDOTHELIAL CELLS DEPENDS ON PRIMING WITH TUMOR NECROSIS FACTOR-α OR INTERFERON-γShock, 1994
- Nitric Oxide-Mediated Apoptosis in Murine MastocytomaBiochemical and Biophysical Research Communications, 1994
- THIOL REDUCING AGENTS MODULATE INDUCED APOPTOSIS IN PORCINE ENDOTHELIAL CELLSShock, 1994
- Selected Treatment Strategies for Septic Shock Based on Proposed Mechanisms of PathogenesisAnnals of Internal Medicine, 1994
- Antioxidants Modulate Induction of Programmed Endothelial Cell Death (Apoptosis) by EndotoxinArchives of Surgery, 1994
- The Discovery of Nitric Oxide in the Vessel WallArchives of Surgery, 1993