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 endothelial cell nitric oxide synthase (ecNOS) expression, Previous studies indicate that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors improve endothelium-dependent relaxation by increasing ecNOS activity, To determine whether HMG CoA reductase inhibitors can prevent hypoxia-mediated down-regulation of ecNOS function and expression, human endothelial cells were exposed to hypoxia (3% O-2) in the presence of HMG CoA reductase inhibitors simvastatin and lovastatin for various durations (0-48 h). Hypoxia decreased ecNOS protein and mRNA levels in a time-dependent manner, resulting in a 4- and 9-fold reduction after 48 h, respectively, In a concentration-dependent manner, simvastatin, and to a lesser extent, lovastatin, prevented the down-regulation of ecNOS expression by hypoxia, Simvastatin-induced changes in ecNOS expression correlated with changes in endothelial NO production and were reversed by treatment with L-mevalonate, Actinomycin D studies revealed that under hypoxic conditions, simvastatin increased ecNOS mRNA half-life from 13 to 38 h. Nuclear run-on studies showed that simvastatin had no effect on repression of ecNOS gene transcription by hypoxia. These results indicate that HMG CoA reductase inhibitors regulate ecNOS function and expression through changes in ecNOS mRNA stability and suggest that treatment with HMG CoA reductase inhibitors may have beneficial effects in patients with hypoxia-mediated pulmonary hypertension.