Assessment of a dual regulatory role for NO in liver regeneration after partial hepatectomy: protection against apoptosis and retardation of hepatocyte proliferation

SPECIFIC AIMSThe role of hepatic nitric oxide (NO) in liver regeneration after partial hepatectomy (PH) was studied in animals expressing a nitric oxide synthase-2 (NOS-2) transgene under the control of the phospho(enol)pyruvate carboxykinase (PEPCK-Tg) promoter after hydrodynamic transfection of murine NOS-2, which targets liver as the main tissue expressing the exogenous gene, and pharmacological administration of NO donors with low decomposition rates (DETA-NO). PEPCK-Tg mice expressed NOS-2 in liver cells under fasting conditions. Early signaling, liver mass recovery, and molecular parameters related to cell proliferation and apoptosis were determined after PH. Preexisting hepatic NO synthesis as well as NO delivery by NO donors impaired early signaling involved in the regenerative response, such as attenuated NF-κB and Stat-3 activation as well as TNF-α and IL-6 release. Under these conditions an insufficient proliferative response was observed, but mouse survival after PH was not compromised. Howeve...