INHIBITION OF 3-HYDROXY-3-METHYLGLUTARYL (HMG)-COA REDUCTASE BLOCKS HYPOXIA-MEDIATED DOWN-REGULATION OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE

Hypoxia induces vasoconstriction, in part, by down-regulating endothel ial cell nitric oxide synthase (ecNOS) expression, Previous studies in dicate that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors improve endothelium-dependent relaxation by increasing ecNO S activity, To determine whether HMG CoA reductase inhibitors can prev ent hypoxia-mediated down-regulation of ecNOS function and expression, human endothelial cells were exposed to hypoxia (3% O-2) in the prese nce of HMG CoA reductase inhibitors simvastatin and lovastatin for var ious durations (0-48 h). Hypoxia decreased ecNOS protein and mRNA leve ls in a time-dependent manner, resulting in a 4- and 9-fold reduction after 48 h, respectively, In a concentration-dependent manner, simvast atin, and to a lesser extent, lovastatin, prevented the down-regulatio n of ecNOS expression by hypoxia, Simvastatin-induced changes in ecNOS expression correlated with changes in endothelial NO production and w ere reversed by treatment with L-mevalonate, Actinomycin D studies rev ealed that under hypoxic conditions, simvastatin increased ecNOS mRNA half-life from 13 to 38 h. Nuclear run-on studies showed that simvasta tin had no effect on repression of ecNOS gene transcription by hypoxia . These results indicate that HMG CoA reductase inhibitors regulate ec NOS function and expression through changes in ecNOS mRNA stability an d suggest that treatment with HMG CoA reductase inhibitors may have be neficial effects in patients with hypoxia-mediated pulmonary hypertens ion.