Modulation of extracellular superoxide dismutase expression by angiotensinII and hypertension

Angiotensin II and hypertension increase vascular oxidant stress. We examin ed how these might affect expression of the extracellular superoxide dismut ase (ecSOD), a major form of vascular SOD. In mice, angiotensin II infusion (1.1 mg/kg for 7 days) increased systolic blood pressure from 107+/-3 to 1 52+/-9 mm Hg and caused a 3-fold increase in ecSOD, but there was no change in the cytosolic Cu/Zn SOD protein, as determined by Western blot analysis . This was associated with a similar increase in ecSOD mRNA as assessed by RNase protection assay and was prevented by losartan. Induction of ecSOD by angiotensin II was not due to hypertension alone, because hypertension cau sed by norepinephrine (5.6 mg.kg(-1).d(-1)) had no effect on ecSOD. Similar ly, exposure of mouse aortas to angiotensin II (100 nmol/L) in organoid cul ture increased ecSOD by approximate to 2-fold. In the organoid culture, ang iotensin II-induced upregulation of ecSOD was prevented by losartan (10 mu mol/L) and PD985059 (30 mu mol/L), a specific inhibitor of p42/44 MAP kinas e kinase. Angiotensin IT activates the NADH/NADPH oxidase; however, dipheny leneiodonium chloride (10 mu mol/L), an inhibitor of this oxidase, did not prevent p42/44 MAP kinase phosphorylation or ecSOD induction by angiotensin II. Finally, in human aortic smooth muscle cells, angiotensin II moderatel y increased transcriptional rate (as assessed by nuclear run-on analysis) b ut markedly increased ecSOD mRNA stability. Thus, angiotensin II increases ecSOD expression independent of hypertension, and this increase involves bo th an increase in ecSOD transcription and stabilization of ecSOD mRNA. This effect of angiotensin II on ecSOD expression may modulate the oxidative st ate of the vessel wall in pathological processes in which the renin-angiote nsin system is activated.